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Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible. Therefore, we aim to validate the association between Z-endoxifen concentration and tamoxifen treatment outcomes, and identify a Z-endoxifen concentration threshold of tamoxifen efficacy, using pharmacometric modeling and simulation. As a first step, the CYP2D6 Endoxifen Percentage Activity Model (CEPAM) cohort was created by pooling data from 28 clinical studies (> 7,000 patients) with measured endoxifen plasma concentrations. After cleaning, data from 6,083 patients were used to develop a nonlinear mixed-effect (NLME) model for tamoxifen and Z-endoxifen pharmacokinetics that includes a conversion factor to allow inclusion of studies that measured total endoxifen but not Z-endoxifen. The final parent-metabolite NLME model confirmed the primary role of CYP2D6, and contributions from body weight, CYP2C9 phenotype, and co-medication with CYP2D6 inhibitors, on Z-endoxifen pharmacokinetics. Future work will use the model to simulate Z-endoxifen concentrations in patients receiving single agent tamoxifen treatment within large prospective clinical trials with long-term survival to identify the Z-endoxifen concentration threshold below which tamoxifen is less efficacious. Identification of this concentration threshold would allow personalized tamoxifen treatment to improve outcomes in patients with hormone receptor-positive breast cancer., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The cytochrome P450 (CYP) family of enzymes plays a central role in the metabolism of many drugs. CYP genes are highly polymorphic, which is known to affect protein levels, but for some low frequent CYP genotypes the correlation between genotype and CYP protein expression is less established. In this study, we determined the CYP2C9, CYP2C19, CYP2D6, and CYP3A5 genotypes of 250 Danish individuals included in a postmortem study. For 116 of the individuals, the hepatic CYP protein levels were investigated by a proteomics approach. Overall, we found the postmortem genetic and proteomic data to be in agreement with those of other studies performed on fresh hepatic tissue, showing the usability of postmortem hepatic tissue for this type of investigation. For less investigated genotypes, we could corroborate previously found results: 1) statistically significantly lower levels of hepatic CYP2C9 protein in individuals carrying the CYP2C9 *3 variant compared with individuals with two wild type (wt) alleles; 2) comparable levels of CYP2C19 in CYP2C19*2/*17 and CYP2C19*1/*2 individuals; 3) reduced CYP2D6 protein levels in heterozygous individuals with the CYP2D6*3 , CYP2D6 *4, and CYP2D6 *5 gene deletion variants; and 4) significantly lower levels of CYP3A5 protein in CYP3A5 *3 homozygous individuals compared with individuals who were heterozygous for the CYP3A5 *3 allele or homozygous individuals for the wt alleles. In conclusion, the use of postmortem tissue significantly increases the access to human specimens for research purposes, and postmortem proteomics can be used to investigate the link between CYP genotypes and hepatic protein expression. SIGNIFICANCE STATEMENT: In tissue samples from a large postmortem cohort ( n = 250) we determined the CYP2C9 , CYP2C19 , CYP2D6 , and CYP3A5 genotypes. Hepatic CYP protein levels were investigated in 116 individuals using a proteomics approach. For common genotypes, we found results similar to previous knowledge, pointing toward the usability of postmortem tissue. For the less investigated genotypes, we were able to corroborate genotype/protein expression correlations. It is a novel approach to use a large postmortem cohort to investigate genetic/protein expression correlations., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: We describe the implementation and ongoing maintenance of CYP2C19 and CYP2D6 focused pharmacogenetic (PGx) testing to guide antidepressant and antianxiety medication prescriptions in a large rural, nonprofit health system., Summary: Depression and anxiety are common psychiatric conditions. Sanford Health implemented PGx testing for metabolism of cytochrome P450 (CYP) isozymes 2C19 and 2D6 in 2014 to inform prescribing for multiple medications, including antidepressant and antianxiety therapies. As guidelines, genotype to phenotype translation, panel offerings, and other resources are updated, we adapt our approach. We make educational and informational materials available to providers and patients. Pharmacogenomic clinical pharmacists review PGx results with discrete values and provide guidance documentation in the electronic medical record. A robust clinical decision support system is in place to provide interruptive alerts, noninterruptive alerts, and genomic indicators. A referral-based interdisciplinary clinic is also available to provide in-depth education to patients regarding PGx results and implications. Additionally, partnering with our health plan has expanded access to PGx testing for patients with anxiety or depression., Conclusion: The implementation and maintenance of Sanford Health's PGx program to guide antidepressant and antianxiety medication use continues to evolve and requires a multipronged approach relying on both human and informatics-based resources., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes involved in drug metabolism. Genetic polymorphism can influence drug metabolism by CYP2D6 such that a therapy is seriously affected by under- or overdosing of drugs. However, a general explanation at the atomistic level for poor activity is missing so far. Here we show for the 20 most common single nucleotide polymorphisms (SNPs) of CYP2D6 that poor metabolism is driven by four mechanisms. We found in extensive all-atom molecular dynamics simulations that the rigidity of the I-helix (central helix), distance between central phenylalanines (stabilizing bound substrate), availability of basic residues on the surface of CYP2D6 (binding of cytochrome P450 reductase), and position of arginine 132 (electron transfer to heme) are essential for an extensive function of the enzyme. These results were applied to SNPs with unknown effects, and potential SNPs that may lead to poor drug metabolism were identified. The revealed molecular mechanisms might be important for other drug-metabolizing cytochrome P450 enzymes.

Purpose: The aim of this study was to examine the ability of sunscreen active ingredients to inhibit in vitro drug metabolism via cytochrome P450 (CYP) enzymes and drug uptake transporters., Methods: Metabolism assays with human liver microsomes were conducted for CYP2C9, CYP2D6 and CYP3A4 using probe substrates warfarin, bufuralol and midazolam, respectively. Uptake transporter assays with transfected cell lines were conducted for OAT3, OCT2 and OATP1B1 with probe substrates estrone-3-sulfate, metformin and rosuvastatin, respectively. Six sunscreen active ingredients, avobenzone, enzacamene, oxybenzone, octinoxate, trolamine, and homosalate, were evaluated up to their aqueous solubility limits in the assays., Results: None of the sunscreen active ingredients inhibited CYP2D6 or CYP3A4 activities in the microsomes at concentration ranges up to tenfold higher than their known clinical total plasma levels. Only enzacamene, oxybenzone and trolamine were found to be inhibitory to CYP2C9 activity with IC 50 values of 14.76, 22.46 and 154.7 µM, respectively. Avobenzone, enzacamene, homosalate and octinoxate were not inhibitory to the uptake transporters at the evaluated concentrations. Oxybenzone was inhibitory to OAT3 and OCT2 with IC 50 values of 39.93 and 42.77 µM, respectively. Trolamine also inhibited uptake in OAT3 and OCT2 transfected cells with IC 50 values of 448.1 and 1376 μM, respectively., Conclusions: Although enzacamene, oxybenzone and trolamine inhibited CYP2C9 and the renal transporters OAT3 and OCT2 in vitro, their IC 50 values exceeded total plasma levels found in clinical studies. Therefore, it is unlikely that these sunscreen active ingredients in sunscreen products will inhibit the metabolism or transport of co-administered drugs in consumers., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Limited evidence exists on the safety of pharmacokinetic interactions of cytochrome P450 (CYP) 2D6 (CYP2D6)-metabolized opioids with antidepressants among older nursing home (NH) residents., Objective: To investigate the associations of concomitant use of CYP2D6-metabolized opioids and antidepressants with clinical outcomes and opioid-related adverse events (ORAEs)., Design: Retrospective cohort study using a target trial emulation framework., Setting: 100% Medicare NH sample linked to Minimum Data Set (MDS) from 2010 to 2021., Participants: Long-term residents aged 65 years and older receiving CYP2D6-metabolized opioids with a disease indication for antidepressant use., Intervention: Initiating CYP2D6-inhibiting versus CYP2D6-neutral antidepressants that overlapped with use of CYP2D6-metabolized opioids for 1 day or more., Measurements: Clinical outcomes were worsening pain, physical function, and depression from baseline to quarterly MDS assessments and were analyzed using modified Poisson regression models. The ORAE outcomes included counts of pain-related hospitalizations and emergency department (ED) visits, opioid use disorder (OUD), and opioid overdose and were analyzed with negative binomial or Poisson regression models. All models were adjusted for baseline covariates via inverse probability of treatment weighting., Results: Among 29 435 identified residents, use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with a higher adjusted rate ratio of worsening pain (1.13 [95% CI, 1.09 to 1.17]) and higher adjusted incidence rate ratios of pain-related hospitalization (1.37 [CI, 1.19 to 1.59]), pain-related ED visit (1.49 [CI, 1.24 to 1.80]), and OUD (1.93 [CI, 1.37 to 2.73]), with no difference in physical function, depression, and opioid overdose., Limitation: Findings are generalizable to NH populations only., Conclusion: Use of CYP2D6-metabolized opioids concomitantly with CYP2D6-inhibiting (vs. CYP2D6-neutral) antidepressants was associated with worsening pain and increased risk for most assessed ORAEs among older NH residents., Primary Funding Source: National Institute on Aging., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-3109.

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Primaquine is essential for the radical cure of Plasmodium vivax malaria and must be metabolized into its bioactive metabolites. Accordingly, polymorphisms in primaquine-metabolizing enzymes can impact the treatment efficacy. This pioneering study explores the influence of monoamine oxidase-A (MAO-A) on primaquine metabolism and its impact on malaria relapses., Methods: Samples from 205 patients with P. vivax malaria were retrospectively analysed by genotyping polymorphisms in MAO-A and cytochrome P450 2D6 (CYP2D6) genes. We measured the primaquine and carboxyprimaquine blood levels in 100 subjects for whom blood samples were available on the third day of treatment. We also examined the relationship between the enzyme variants and P. vivax malaria relapses in a group of subjects with well-documented relapses., Results: The median carboxyprimaquine level was significantly reduced in individuals carrying low-expression MAO-A alleles plus impaired CYP2D6. In addition, this group experienced significantly more P. vivax relapses. The low-expression MAO-A status was not associated with malaria relapses when CYP2D6 had normal activity. This suggests that the putative carboxyprimaquine contribution is irrelevant when the CYP2D6 pathway is fully active., Conclusions: We found evidence that the low-expression MAO-A variants can potentiate the negative impact of impaired CYP2D6 activity, resulting in lower levels of carboxyprimaquine metabolite and multiple relapses. The findings support the hypothesis that carboxyprimaquine may be further metabolized through CYP-mediated pathways generating bioactive metabolites that act against the parasite., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Human cytochrome P450 (CYP) proteins metabolize 75% of small-molecule pharmaceuticals, which makes structure-based modeling of CYP metabolism and inhibition, bolstered by the current availability of X-ray crystal structures of CYP globular catalytic domains, an attractive prospect. Accounting for this broad metabolic capacity is a combination of the existence of multiple different CYP proteins and the capacity of a single CYP protein to metabolize multiple different small molecules. It is thought that structural plasticity and flexibility contribute to this latter property; therefore, incorporating diverse conformational states of a particular CYP is likely an important consideration in structure-based CYP metabolism and inhibition modeling. While all-atom explicit-solvent molecular dynamics simulations can be used to generate conformational ensembles under biologically relevant conditions, existing CYP crystal structures are of the globular domain only, whereas human CYPs contain N-terminal transmembrane and linker peptides that anchor the globular catalytic domain to the endoplasmic reticulum. To determine whether this can cause significant differences in the sampled binding site conformations, microsecond scale all-atom explicit-solvent molecular dynamics simulations of the CYP2D6 globular domain in an aqueous environment were compared with those of the full-length protein anchored in a POPC lipid bilayer. While bilayer-anchoring damped some structural fluctuations in the globular domain relative to the aqueous simulations, none of the affected residues included binding site pocket residues. Furthermore, clustering of molecular dynamics snapshots based on either pairwise binding site pocket RMSD or volume differences demonstrated a lack of separation of snapshots from the two simulation conditions into different clusters. These results suggest the substantially simpler and computationally cheaper aqueous simulation approach can be used to generate a relevant conformational ensemble of the CYP2D6 binding site for structure-based metabolism and inhibition modeling.

Background: Nardosinone, a major extract of Rhizoma nardostachyos, plays a vital role in sedation, neural stem cell proliferation, and protection of the heart muscle. However, the huge potential of nardosinone in regulating lipid metabolism and gut microbiota has not been reported, and its potential mechanism has not been studied., Purpose: To explore the regulation of nardosinone on liver lipid metabolism and gut microbiota., Methods: In this study, the role of nardosinone in lipid metabolism was investigated in vitro and in vivo by adding it to mouse feed and HepG2 cell culture medium. And 16S rRNA gene sequencing was used to explore its regulatory effect on gut microbiota., Results: Results showed that nardosinone could improve HFD-induced liver injury and abnormal lipid metabolism by promoting mitochondrial energy metabolism in hepatocytes, alleviating oxidative stress damage, and regulating the composition of the gut microbiota. Mechanistically, combined with network pharmacology and reverse docking analysis, it was predicted that CYP2D6 was the target of nardosinone, and the binding was verified by cellular thermal shift assay (CETSA)., Conclusions: This study highlights a novel mechanism function of nardosinone in regulating lipid metabolism and gut microbiota. It also predicts and validates CYP2D6 as a previously unknown regulatory target, which provides new possibilities for the application of nardosinone and the treatment of metabolic-associated fatty liver disease., Competing Interests: Declaration of competing interest All authors of the paper entitled “Nardosinone relieves metabolic-associated fatty liver disease and promotes energy metabolism through targeting CYP2D6” declare that there is no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Cytochrome P450 2D6 (CYP2D6) plays a crucial role in metabolizing approximately 20% of medications prescribed clinically. This enzyme is encoded by the CYP2D6 gene, known for its extensive polymorphism with over 170 catalogued haplotypes or star alleles, which can have a profound impact on drug efficacy and safety. Despite its importance, a gap exists in the global genomic databases, which are predominantly representative of European ancestries, thereby limiting comprehensive knowledge of CYP2D6 variation in ethnically diverse populations. In an effort to bridge this knowledge gap, we focused on elucidating the CYP2D6 variation landscape within a multi-ethnic Asian cohort, encompassing individuals of Chinese, Malay, and Indian descent. Our study comprised data analysis of 1850 whole genomes from the SG10K_Health dataset using an in-house consensus algorithm, which integrates the capabilities of Cyrius, Aldy, and StellarPGx. This analysis unveiled distinct population-specific star-allele distribution trends, highlighting the unique genetic makeup of the Singaporean population. Significantly, 46% of our cohort harbored actionable CYP2D6 variants-those with direct implications for drug dosing and treatment strategies. Furthermore, we identified 14 potential novel CYP2D6 star-alleles, of which 7 were observed in multiple individuals, suggesting their broader relevance. Overall, our study contributes novel data on CYP2D6 genetic variations specific to the Southeast Asian context. The findings are instrumental for the advancement of pharmacogenomics and personalized medicine, not only in Southeast Asia but also in other regions with comparable genetic diversity., (© 2024. The Author(s).)

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I 2  = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes., (© 2024. The Author(s).)

Cytochrome P450 (CYP) enzymes are involved in the metabolism of approximately 75% of marketed drugs. Inhibition of the major drug-metabolizing P450s could alter drug metabolism and lead to undesirable drug-drug interactions. Therefore, it is of great significance to explore the inhibition of P450s in drug discovery. Currently, machine learning including deep learning algorithms has been widely used for constructing in silico models for the prediction of P450 inhibition. These models exhibited varying predictive performance depending on the use of machine learning algorithms and molecular representations. This leads to the difficulty in the selection of appropriate models for practical use. In this study, we systematically evaluated the conventional machine learning and deep learning models for three major P450 enzymes, CYP3A4, CYP2D6, and CYP2C9 from several perspectives, such as algorithms, molecular representation, and data partitioning strategies. Our results showed that the XGBoost and CatBoost algorithms coupled with the combined fingerprint/physicochemical descriptor features exhibited the best performance with Area Under Curve (AUC)  of 0.92, while the deep learning models were generally inferior to the conventional machine learning models (average AUC reached 0.89) on the same test sets. We also found that data volume and sampling strategy had a minor effect on model performance. We anticipate that these results are helpful for the selection of molecular representations and machine learning/deep learning algorithms in the P450 model construction and the future model development of P450 inhibition., (© 2024 John Wiley & Sons Ltd.)

Background: Several opioids have pharmacogenetic and drug-drug interactions which may compromise their analgesic effectiveness, but are not routinely implemented into supportive pain management. We hypothesized that CYP2D6 phenotypes and concomitant use of CYP2D6 substrates or inhibitors would correlate with opioid analgesic outcomes., Materials and Methods: An observational cross-sectional study was conducted with 263 adult chronic non cancer pain (CNCP) patients from a real-world pain unit under long-term CYP2D6-related opioid treatment (tramadol, hydromorphone, tapentadol or oxycodone). Metabolizer phenotype (ultrarapid [UM], normal [NM], intermediate [IM] or poor [PM]) was determined by the CYP2D6 genotype. The socio-demographic (sex, age, employment status), clinical (pain intensity and relief, neuropathic component, quality of life, disability, anxiety and depression), pharmacological (opioid doses and concomitant pharmacotherapy) and safety (adverse events) variables were recorded., Results: The whole population (66 % female, 65 (14) years old, 70 % retired and 63 % attended for low back pain) were classified as PM (5 %), IM (32 %), NM (56 %) and UM (6 %). Multiple linear and logistic regressions showed higher pain intensity and neuropathic component at younger ages when using any CYP2D6 substrate (p = 0.022) or inhibitor (p = 0.030) drug, respectively, with poorer pain relief when CYP2D6 inhibitors (p=0.030) were present., Conclusion: The concomitant use of CYP2D6 substrates or inhibitors during opioid therapy for CNCP may result in lack of analgesic effectiveness. This aspect could be relevant for pharmacological decision making during CNCP management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: The CYP2D6 gene exhibits significant polymorphism, contributing to variability in responses to drugs metabolized by CYP2D6. While CYP2D6*2 and CYP2D6*35 are presently designated as alleles encoding normal metabolism, this classification is based on moderate level evidence. Additionally, the role of the formerly called "enhancer" single nucleotide polymorphism (SNP) rs5758550 is unclear. In this study, the impacts of CYP2D6*2, CYP2D6*35 and rs5758550 on CYP2D6 activity were investigated using risperidone clearance as CYP2D6 activity marker., Methods: A joint parent-metabolite population pharmacokinetic model was used to describe 1,565 serum concentration measurements of risperidone and 9-hydroxyrisperidone in 512 subjects. Risperidone population clearance was modeled as the sum of a CYP2D6-independent clearance term and the partial clearances contributed from each individually expressed CYP2D6 allele or haplotype. In addition to the well-characterized CYP2D6 alleles (*3-*6, *9, *10 and *41), *2, *35 and two haplotypes assigned as CYP2D6*2-rs5758550G and CYP2D6*2-rs5758550A were evaluated., Results: Each evaluated CYP2D6 allele was associated with significantly lower risperidone clearance than the reference normal function allele CYP2D6*1 (p < 0.001). Further, rs5758550 differentiated the effect of CYP2D6*2 (p = 0.005). The haplotype-specific clearances for CYP2D6*2-rs5758550A, CYP2D6*2-rs5758550G and CYP2D6*35 were estimated to 30%, 66% and 57%, respectively, relative to the clearance for CYP2D6*1. Notably, rs5758550 is in high linkage disequilibrium (R 2  > 0.85) with at least 24 other SNPs and cannot be assigned as a functional SNP., Conclusion: CYP2D6*2 and CYP2D6*35 encode reduced risperidone clearance, and the extent of reduction for CYP2D6*2 is differentiated by rs5758550. Genotyping of these haplotypes might improve the precision of genotype-guided prediction of CYP2D6-mediated clearance., (© 2024. The Author(s).)

Schizophrenia spectrum disorders (SSD) are a group of diseases characterized by one or more abnormal features in perception, thought processing and behavior. Patients suffering from SSD are at risk of developing life-threatening complications. Pharmacogenetic studies have shown promising results on personalized treatment of psychosis. In the current study, 103 patients diagnosed with SSD treated with risperidone as antipsychotic monotherapy were enrolled. Socio-demographics and clinical data were recorded, and laboratory tests and genotyping standard procedure for cytochrome P450 (CYP) 2D6*4 were performed. Patients were evaluated by the Positive and Negative Syndrome Scale (PANSS) on admission and at discharge. Based on the reduction in the PANSS total score, subjects were divided into non-responders, partial responders and full responders. Only 11 subjects had a full response to risperidone (10.67%), 53 subjects (51.45%) had a partial response, and 39 participants (37.86%) were non-responders. Patients at first episode psychosis showed significantly higher levels of blood glucose and prolactin levels, while chronic patients showed significantly higher LDL levels. Adverse drug reactions (ADR) such as tremor and stiffness significantly correlated with genetic phenotypes ( p = 0.0145). While CYP2D6 showed no impact on treatment response, ADR were significantly more frequent among poor and intermediate metabolizers.

Background: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing., Methods: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses., Findings: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population., Interpretation: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach., Funding: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit., Competing Interests: Declaration of interests The PMEDA consortium is funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-C&T-B-099) and “the Fundamental Research Funds for the Central Universities” (Peking University Medicine Fund for world's leading discipline or discipline cluster development, BMU2022DJXK007). WY, YL, Yu S, JG, ZK, and YZ disclose that there is a planned and pending patent related to a device for predicting the treatment outcome of paroxetine, which is relevant to the content of this manuscript. Other authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Fatal drug overdoses often involve multiple co-intoxicants, including opioids. Hydrocodone, the most prescribed opioid for pain management, is metabolized to the active metabolite hydromorphone by hepatic CYP2D6. Inhibition of CYP2D6 by other compounds can disrupt the analgesic properties of hydrocodone and extend its half-life. Diphenhydramine is an over-the-counter cold medication and is known to inhibit CYP2D6 activity., Case Presentation: A woman in her late 50s was prescribed hydrocodone/acetaminophen (Norco ® 10/325). Days before her death, she began taking diphenhydramine for cold symptoms. A post-mortem toxicology report detected the following compounds by High Performance Liquid Chromatography/Time of Flight-Mass Spectrometry (LC/TOF-MS) analysis: acetaminophen (14 μg/mL), hydrocodone (410 ng/mL), dihydrocodeine (24 ng/mL), and diphenhydramine (150 ng/mL). Hydromorphone was not detected (<2 ng/mL). All compounds were detected in therapeutic concentrations, except for hydrocodone, which was present at lethal concentrations., Conclusions: This case highlights a fatal drug-drug interaction between hydrocodone and diphenhydramine. The estimated total body burden of hydrocodone was 6- to 12-fold higher than acetaminophen, which is unexpected, as these two drugs were administered as a single formulation and have similar half-lives. Furthermore, hydromorphone was undetectable. Taken together, these findings are highly suggestive of a fatal opioid overdose precipitated by diphenhydramine., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Medications are frequently prescribed for patients with irritable bowel syndrome (IBS) or disorders of gut brain interaction. The level of drug metabolism and modifications in drug targets determine medication efficacy to modify motor or sensory function as well as patient response outcomes., Areas Covered: The literature search included PubMed searches with the terms: pharmacokinetics, pharmacogenomics, epigenetics, clinical trials, irritable bowel syndrome, disorders of gut brain interaction, and genome-wide association studies. The main topics covered in relation to irritable bowel syndrome were precision medicine, pharmacogenomics related to drug metabolism, pharmacogenomics related to mechanistic targets, and epigenetics., Expert Opinion: Pharmacogenomics impacting drug metabolism [CYP 2D6 (cytochrome P450 2D6) or 2C19 (cytochrome P450 2C19)] is the most practical approach to precision medicine in the treatment of IBS. Although there are proof of concept studies that have documented the importance of genetic modification of transmitters or receptors in altering responses to medications in IBS, these principles have rarely been applied in patient response outcomes. Genome-wide association (GWAS) studies have now documented the association of symptoms with genetic variation but not the evaluation of treatment responses. Considerably more research, particularly focused on patient response outcomes and epigenetics, is essential to impact this field in clinical medicine.

Objective: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine., Methods: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity., Results: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype ( p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid E max model. Spearman correlations were significant ( p < 0.03) for ibogaine but not noribogaine with QTc ( p = 0.109) and cerebellar effects ( p = 0.668); neither correlated with the severity of opioid withdrawal symptoms., Conclusions: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized anxiety disorder, and panic disorder. Venlafaxine is metabolized to the active metabolite desvenlafaxine mainly by CYP2D6. Genetic polymorphism of CYP2D6 and coadministration with other medications can significantly affect the pharmacokinetics and/or pharmacodynamics of venlafaxine and its active metabolite. This study aimed to establish the PBPK models of venlafaxine and its active metabolite related to CYP2D6 genetic polymorphism and to predict drug-drug interactions (DDIs) with clarithromycin and paroxetine in different CYP2D6 genotypes. Clinical pharmacogenomic data for venlafaxine and desvenlafaxine were collected to build the PBPK model. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) characteristics of respective compounds were obtained from previously reported data, predicted by the PK-Sim ® software, or optimized to capture the plasma concentration-time profiles. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and plasma concentration-time profiles to the observed data. Predicted plasma concentration-time profiles of venlafaxine and its active metabolite were visually similar to the observed profiles and all predicted AUC and C max values for respective compounds were included in the twofold error range of observed values in non-genotyped populations and different CYP2D6 genotypes. When clarithromycin or clarithromycin plus paroxetine was concomitantly administered, predicted plasma concentration-time profiles of venlafaxine properly captured the observed profiles in two different CYP2D6 genotypes and all predicted DDI ratios for AUC and C max were included within the acceptance range. Consequently, the present model successfully captured the pharmacokinetic alterations of venlafaxine and its active metabolite according to CYP2D6 genetic polymorphism as well as the DDIs between venlafaxine and two CYP inhibitors. The present model can be used to predict the pharmacokinetics of venlafaxine and its active metabolite considering different races, ages, coadministered drugs, and CYP2D6 activity of individuals and it can contribute to individualized pharmacotherapy of venlafaxine., (© 2024. The Pharmaceutical Society of Korea.)

Background and Objective: Viloxazine extended-release (ER) [Qelbree ® ] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics., Methods: Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers., Results: The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (C max ), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC t ), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC ∞ ) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan C max , AUC t, and AUC ∞ , respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam C max , AUC t, and AUC ∞ , respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were C max 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC 0-24 125.66 (105.36-149.87))., Conclusion: Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile., (© 2024. The Author(s).)

Dapoxetine is a selective serotonin reuptake inhibitor (SSRI) used to treat premature ejaculation (PE), and is mainly metabolized by CYP2D6, CYP3A4, and flavin-containing monooxygenase 1. The purpose of the study was to evaluate the effect of CYP2D6 polymorphism on the pharmacokinetics of dapoxetine in healthy Chinese men. Thirty-nine subjects who received a single oral dose of 30 mg dapoxetine hydrochloride were classified based on their CYP2D6 genotype: *1/*1 (n = 9), *1/*41 (n = 1), *1/*10 (n = 12), *10/*41 (n = 3), or *10/*10 (n = 14). The difference in pharmacokinetic parameters between different genotype groups was analyzed and then scored according to the activity score system. Compared with the wild-type subjects of CYP2D6 *1/*1, the peak plasma concentration (C max ) and the area under the plasma drug concentration-time curve (AUC inf ) of dapoxetine in the *10/*10 and *10/*41 groups were notably increased (P ≤ .05). Significant differences in C max , AUC, volume of distribution/bioavailability (V/F) and clearance/bioavailability (CL/F) were observed among dapoxetine activity score groups (P ≤ .05). The AUC inf was increased significantly (154% and 89.73%, P ≤ .05) and the C max was increased significantly (73.45% and 42.67%, P ≤ .05) in CYP2D6 *10/*41 subjects, compared with CYP2D6 *1/*1 and *1/*10 subjects. The results obtained indicated that CYP2D6 *10 and *41 polymorphisms have significant effects on the pharmacokinetic properties of dapoxetine., (© 2023, The American College of Clinical Pharmacology.)

This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in healthy African volunteers to understand the effect of allelic variants of the human cytochrome P450 2D6 (CYP2D6) enzyme, namely the diplotypes of CYP2D6*1/*2 (*1*1, *1*2, *2*2) and the genotypes of CYP2D6*17*17 and CYP2D6*29*29. Overall, 28 adults were included and split into 3 cohorts after genotype screening: CYP2D6*1/*2 (n = 12), CYP2D6*17*17 (n = 12), and CYP2D6*29*29 (n = 4). Each subject received a single oral dose of dextromethorphan 30 mg syrup on day 1 and desipramine 50 mg tablet on day 8. The PK parameters of area under the plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUC last ), and extrapolated to infinity (AUC inf ), and the maximum plasma concentration (C max ) were determined. For both dextromethorphan and desipramine, AUC inf and C max were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts, as compared with subjects in the CYP2D6*1/*2 diplotype cohort and with normal metabolizers from the literature. All PK parameters, including AUC inf , C max , and the elimination half-life, followed a similar trend: CYP2D6*17*17 > CYP2D6*29*29 > CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts, when compared with subjects in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except in 1 subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicate that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5-10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings., (© 2023, The American College of Clinical Pharmacology.)

To investigate the pharmacokinetic and pharmacodynamic profiles of volunteers carrying CYP2D6 genotypes with unknow metabolic phenotypes, a total of 22 volunteers were recruited based on the sequencing results. Peripheral blood and urine samples were collected at specific time points after oral administration of metoprolol. A validated high-performance liquid chromatography (HPLC) method was used to determine the concentrations of metoprolol and α-hydroxymetoprolol. Blood pressure and electrocardiogram were also monitored. The results showed that the main pharmacokinetic parameters of metoprolol in CYP2D6*1/*34 carriers are similar to those in CYP2D6*1/*1 carriers. However, in individuals carrying the CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 genotypes, the area under the curve (AUC) and half-life (t1/2) of metoprolol increased by 2-3 times compared to wild type. The urinary metabolic ratio of metoprolol in these genotypes is consistent with the trends observed in plasma samples. Therefore, CYP2D6*1/*34 can be considered as normal metabolizers, while CYP2D6*10/*87, CYP2D6*10/*95, and CYP2D6*97/*97 are intermediate metabolizers. Although the blood concentration of metoprolol has been found to correlate with CYP2D6 genotype, its blood pressure-lowering effect reaches maximum effectiveness at a reduction of 25 mmHg. Furthermore, P-Q interval prolongation and heart rate reduction are not positively correlated with metoprolol blood exposure. Based on the pharmacokinetic-pharmacodynamic model, this study clarified the properties of metoprolol in subjects with novel CYP2D6 genotypes and provided important fundamental data for the translational medicine of this substrate drug., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The objective of this case report is to illustrate pharmacogenomics (PGx)-guided oxycodone treatment, given the conflicting data on the analgesic response from oxycodone in Cytochrome P450 (CYP)2D6 poor metabolizers (PMs). PGx-guided therapy can help improve treatment outcomes. This case report describes a 58-year-old patient who was prescribed oxycodone for chronic pain management. The patient presented with a history of inadequate pain control despite analgesic treatment with oxycodone (morphine milliequivalent [MME] = 22.5). Pharmacogenetic testing revealed that the patient was a CYP2D6 Poor Metabolizer (PM), which may shed light on the observed lack of analgesic response to oxycodone. The clinical pharmacist recommended switching to an alternative opioid not metabolized via the CYP2D6 pathway. The patient was subsequently switched to hydromorphone (MME = 16), resulting in improved pain control and fewer side effects. The newer hydromorphone dose accounted for a 30% MME dose reduction. The patient's initial average and worst pain score were 7 and 9 out of 10, respectively, per the numeric rating scale (NRS). Upon follow-up with the patient in two weeks, her average and worst pain scores improved to 3 and 3.5 out of 10, respectively, per the NRS. Further PGx testing results led to an overall positive outcome, such as her willingness to participate in physical therapy as a result of improved pain scores. This case highlights the importance of considering individual variability in drug metabolism when prescribing medications, particularly opioids such as oxycodone, to ensure optimal therapeutic outcomes and minimize the risk of adverse events in CYP2D6 PMs.

Objectives: The aim of this prospective study was to compare perioperative opioid use in women by status of CYP2D6, a highly polymorphic pharmacogene relevant to opioid metabolism., Methods: Patients undergoing laparotomy were prospectively recruited and provided a preoperative saliva swab for a pharmacogenomic (PGx) gene panel. Postoperative opioid usage and pain scores were evaluated via chart review and a phone survey. Pharmacogenes known to be relevant to opioid metabolism were genotyped, and opioid metabolizing activity predicted by CYP2D6 genotyping. Patient and procedural factors were compared using Fisher's exact and Kruskal-Wallis tests., Results: The 96 enrolled patients were classified as ultra-rapid (N = 3, 3%), normal (58, 60%), intermediate (27, 28%), and poor (8, 8%) opioid metabolizers. There was no difference in surgical complexity across CYP2D6 categories (p = 0.61). Morphine Milligram Equivalents (MME) consumed during the first 24 h after peri-operative suite exit were significantly different between groups: ultrarapid metabolizers had the highest median MME (75, IQR 45-88) compared to the other three groups (normal metabolizers 23 [8-45], intermediate metabolizers 48 [20-63], poor metabolizers 31 [12-53], p = 0.03). Opioid requirements were clinically greater in ultrarapid metabolizers during the second 24 h and last 24 h but were statistically similar (p = 0.07). There was no difference in MME prescribed at discharge (p = 0.22) or patient satisfaction with pain control (p = 0.64) between groups., Conclusions: A positive association existed between increased CYP2D6 activity and in-hospital opioid requirements, especially in the first 24 h after surgery. This provides important information to further individualize opioid prescriptions for patients undergoing laparotomy for gynecologic pathology., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

To assess the effect of Rehmannioside A on CYP450s activity and to estimate its inhibitory properties.The effect of Rehmannioside A on the activity of major CYP450s in human liver microsomes (HLMs) was assessed with the corresponding substrates and marker reactions, and compared with a blank control and the respective inhibitors. Suppression of CYP3A4, 2C9 and 2D6 was assessed by the dose-dependent assay and fitted with non-competitive or competitive inhibition models. The inhibition of CYP3A4 was determined in a time-dependent manner.Rehmannioside A suppressed the activity of CYP3A4, 2C9, and 2D6 with IC 50 values of 10.08, 12.62, and 16.43 μM, respectively. Suppression of CYP3A4 was fitted to a non-competitive model with K i value of 5.08 μM, whereas CYP2C9 and 2D6 were fitted to a competitive model with K i values of 6.25 and 8.14 μM. Additionally, the inhibitory effect on CYP3A4 was time-dependent with K I value of 8.47 μM -1 and a K inact of 0.048 min -1 . In vitro suppression of CYP3A, 2C9 and 2D6 by Rehmannioside A indicated that Rehmannioside A or its source herbs may interact with drugs metabolised by these CYP450s, which could guide the clinical application.

Background: We investigated the effect of a 5-day low-dose ritonavir therapy, as it is used in the treatment of COVID-19 with nirmatrelvir/ritonavir, on the pharmacokinetics of three factor Xa inhibitors (FXaI). Concurrently, the time course of the activities of the cytochromes P450 (CYP) 3A4, 2C19, and 2D6 was assessed., Methods: In an open-label, fixed sequence clinical trial, the effect and duration of a 5-day oral ritonavir (100 mg twice daily) treatment on the pharmacokinetics of three oral microdosed FXaI (rivaroxaban 25 µg, apixaban 25 µg, and edoxaban 50 µg) and microdosed probe drugs (midazolam 25 µg, yohimbine 50 µg, and omeprazole 100 µg) was evaluated in eight healthy volunteers. The plasma concentrations of all drugs were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods and pharmacokinetics were analysed using non-compartmental analyses., Results: Ritonavir increased the exposure of apixaban, edoxaban, and rivaroxaban, but to a different extent the observed area under the plasma concentration-time curve (geometric mean ratio 1.29, 1.46, and 1.87, respectively). A strong CYP3A4 inhibition (geometric mean ratio > 10), a moderate CYP2C19 induction 2 days after ritonavir (0.64), and no alteration of CYP2D6 were observed. A CYP3A4 recovery half-life of 2.3 days was determined., Conclusion: This trial with three microdosed FXaI suggests that at most the rivaroxaban dose should be reduced during short-term ritonavir, and only in patients receiving high maintenance doses. Thorough time series analyses demonstrated differential effects on three different drug-metabolising enzymes over time with immediate profound inhibition of CYP3A4 and only slow recovery after discontinuation., Clinical Trial Registration: EudraCT number: 2021-006643-39., (© 2024. The Author(s).)

Tree shrews are a nonprimate species used in a range of biomedical studies. Recent genome analysis of tree shrews found that the sequence identities and the numbers of genes of cytochrome P450 (CYP or P450), an important family of drug-metabolizing enzymes, are similar to those of humans. However, tree shrew P450s have not yet been sufficiently identified and analyzed. In this study, novel CYP2D8a and CYP2D8b cDNAs were isolated from tree shrew liver and were characterized, along with human CYP2D6, dog CYP2D15, and pig CYP2D25. The amino acid sequences of these tree shrew CYP2Ds were 75%-78% identical to human CYP2D6, and phylogenetic analysis showed that they were more closely related to human CYP2D6 than rat CYP2Ds, similar to dog and pig CYP2Ds. For tree shrew CYP2D8b, two additional transcripts were isolated that contained different patterns of deletion. The gene and genome structures of CYP2Ds are generally similar in dogs, humans, pigs, and tree shrews. Tree shrew CYP2D8a mRNA was most abundantly expressed in liver, among the tissue types analyzed, similar to dog CYP2D15 and pig CYP2D25 mRNAs. Tree shrew CYP2D8b mRNA was also expressed in liver, but at a level 7.3-fold lower than CYP2D8a mRNA. Liver microsomes and recombinant protein of both tree shrew CYP2Ds metabolized bufuralol and dextromethorphan, selective substrates of human CYP2D6, but the activity level of CYP2D8a greatly exceeded that of CYP2D8b. These results suggest that tree shrew CYP2D8a and CYP2D8b are functional drug-metabolizing enzymes, of which CYP2D8a is the major CYP2D in liver. SIGNIFICANCE STATEMENT: Novel tree shrew CYP2D8a and CYP2D8b cDNAs were isolated from liver. Their amino acid sequences were 75%-78% identical to human CYP2D6. For CYP2D8b, two additional transcripts contained different patterns of deletion. Tree shrew CYP2D8a mRNA was abundantly expressed in liver, similar to dog CYP2D15 and pig CYP2D25 mRNAs. Recombinant tree shrew CYP2Ds catalyzed the oxidation of bufuralol and dextromethorphan. Tree shrew CYP2D8a and CYP2D8b are functional drug-metabolizing enzymes, of which CYP2D8a is the major CYP2D in liver., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Aims: The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6-mediated metabolism of risperidone in patients with known CYP2D6 genotypes., Methods: The study included therapeutic drug monitoring (TDM) data from CYP2D6-genotyped patients treated with risperidone. Risperidone and 9-hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full-scan high-resolution mass spectrometry files was applied for semi-quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9-hydroxyrisperidone-to-risperidone ratio., Results: A total of 229 patients were included. Highly significant, positive correlationswere observed between all solanidine MRs and the 9-hydroxyrisperidone-to-risperidone ratio (ρ > 0.6, P < .0001). The strongest correlation was observed for the M444-to-solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72-0.77, P < .0001)., Conclusion: The present study shows strong, positive correlations between solanidine metabolism and CYP2D6-mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Oxycodone is one of the most commonly used opioids to treat moderate to severe pain. It is metabolized mainly by CYP3A4 and CYP2D6, while only a small fraction of the dose is excreted unchanged into the urine. Oxymorphone, the metabolite primarily formed by CYP2D6, has a 40- to 60-fold higher mu-opioid receptor affinity than the parent compound. While CYP2D6-mediated gene-drug-interactions (GDIs) and drug-drug interactions (DDIs) are well-studied, they only account for a portion of the variability in oxycodone and oxymorphone exposure. The combined impact of CYP2D6-mediated GDIs and DDIs, CYP3A4-mediated DDIs, and UGT2B7 GDIs is not fully understood yet and hard to study in head-to-head clinical trials given the relatively large number of scenarios. Instead, we propose the use of a physiologically-based pharmacokinetic model that integrates available information on oxycodone's metabolism to characterize and predict the impact of DDIs and GDIs on the exposure of oxycodone and its major, pharmacologically-active metabolite oxymorphone. To this end, we first developed and verified a PBPK model for oxycodone and its metabolites using published clinical data. The verified model was then applied to determine the dose-exposure relationship of oxycodone and oxymorphone stratified by CYP2D6 and UGT2B7 phenotypes respectively, and administered perpetrators of CYP-based drug interactions. Our simulations demonstrate that the combination of CYP2D6 UM and a UGT2B7Y (268) mutation may lead to a 2.3-fold increase in oxymorphone exposure compared to individuals who are phenotyped as CYP2D6 NM / UGT2B7 NM. The extent of oxymorphone exposure increases up to 3.2-fold in individuals concurrently taking CYP3A4 inhibitors, such as ketoconazole. Inhibition of the CYP3A4 pathway results in a relative increase in the partial metabolic clearance of oxycodone to oxymorphone. Oxymorphone is impacted to a higher extent by GDIs and DDIs than oxycodone. We predict oxymorphone exposure to be highest in CYP2D6 UMs/UGT2B7 PMs in the presence of ketoconazole (strong CYP3A4 index inhibitor) and lowest in CYP2D6 PMs/UGT2B7 NMs in the presence of rifampicin (strong CYP3A4 index inducer) covering a 55-fold exposure range., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Evaluating the safety of primaquine (PQ) during breastfeeding requires an understanding of its pharmacokinetics (PKs) in breast milk and its exposure in the breastfed infant. Physiologically-based PK (PBPK) modeling is primed to assess the complex interplay of factors affecting the exposure of PQ in both the mother and the nursing infant. A published PBPK model for PQ describing the metabolism by monoamine oxidase A (MAO-A; 90% contribution) and cytochrome P450 2D6 (CYP2D6; 10%) in adults was applied to predict the exposure of PQ in mothers and their breastfeeding infants. Plasma exposures following oral daily dosing of 0.5 mg/kg in the nursing mothers in a clinical lactation study were accurately captured, including the observed ranges. Reported infant daily doses based on milk data from the clinical study were used to predict the exposure of PQ in breastfeeding infants greater than or equal to 28 days. On average, the predicted exposures were less than or equal to 0.13% of the mothers. Furthermore, in simulations involving neonates less than 28 days, PQ exposures remain less than 0.16% of the mothers. Assuming that MAO-A increases slowly with age, the predicted relative exposure of PQ remains low in neonates (<0.46%). Thus, the findings of our study support the recommendation made by the authors who reported the results of the clinical lactation study, that is, that when put into context of safety data currently available in children, PQ should not be withheld in lactating women as it is unlikely to cause adverse events in breastfeeding infants greater than or equal to 28 days old., (© 2023 Certara UK. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Psychiatric disorders burden the peripartum period, often requiring psychopharmacological treatment, including antidepressants. Efficacy and tolerability of antidepressants are influenced by the physiological changes of the peripartum and individual metabolic profiles, which in turn can be modified by pregnancy. The objective of this study is to assess the relationship between antidepressants' pharmacokinetic profiles during pregnancy and individual metabolic profiles, along with the efficacy of the treatment., Methods: In total 87 outpatients with diagnoses of bipolar disorder, major depression, anxiety, obsessive-compulsive disorder and post-traumatic stress disorder who required antidepressant treatment during pregnancy were recruited. Genotyping analysis of hepatic cytochrome P450 (CYPs) individual isoforms was performed. Antidepressants' blood concentrations and psychometric assessments were collected at five time points. Antidepressants' cord blood concentrations were assessed at birth., Results: Sertraline showed greater stability in plasma concentrations and a lower placental penetrance index. Most of the antidepressants' concentrations below the therapeutic range were found in women with an extensive/ultrarapid metabolic profile. Antidepressants mainly metabolized by CYP2C19 were less frequently below the therapeutic range compared with antidepressants metabolized by CYP2D6., Conclusions: Pregnancy modulates cytochrome activity and drugs' pharmacokinetics. Genotyping analysis of CYPs isoforms and therapeutic drug monitoring might be used to guide clinicians in a well-tolerated treatment of psychiatric symptoms in pregnant women., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The inhibitory effect of Apatinib on cytochrome P450 (CYP450) enzymes has been studied. However, it is unknown whether the inhibition is related to the major metabolites, M1-1, M1-2 and M1-6., Methods: A 5-in-1 cocktail system composed of CYP2B6/Cyp2b1, CYP2C9/Cyp2c11, CYP2E1/Cyp2e1, CYP2D6/Cyp2d1 and CYP3A/Cyp3a2 was used in this study. Firstly, the effects of APA and its main metabolites on the activities of HLMs, RLMs and recombinant isoforms were examined. The reaction mixture included HLMs, RLMs or recombinant isoforms (CYP3A4.1, CYP2D6.1, CYP2D6.10 or CYP2C9.1), analyte (APA, M1-1, M1-2 or M1-6), probe substrates. The reactions were pre-incubated for 5 min at 37 °C, followed by the addition of NAPDH to initiate the reactions, which continued for 40 min. Secondly, IC 50 experiments were conducted to determine if the inhibitions were reversible. The reaction mixture of the "+ NADPH Group" included HLMs or RLMs, 0 to 100 of μM M1-1 or M1-2, probe substrates. The reactions were pre-incubated for 5 min at 37 °C, and then NAPDH was added to initiate reactions, which proceeded for 40 min. The reaction mixture of the "- NADPH Group" included HLMs or RLMs, probe substrates, NAPDH. The reactions were pre-incubated for 30 min at 37 °C, and then 0 to 100 μM of M1-1 or M1-2 was added to initiate the reactions, which proceeded for 40 min. Finally, the reversible inhibition of M1-1 and M1-2 on isozymes was determined. The reaction mixture included HLMs or RLMs, 0 to 10 μM of M1-1 or M1-2, probe substrates with concentrations ranging from 0.25K m to 2K m ., Results: Under the influence of M1-6, the activity of CYP2B6, 2C9, 2E1 and 3A4/5 was increased to 193.92%, 210.82%, 235.67% and 380.12% respectively; the activity of CYP2D6 was reduced to 92.61%. The inhibitory effects of M1-1 on CYP3A4/5 in HLMs and on Cyp2d1 in RLMs, as well as the effect of M1-2 on CYP3A in HLMs, were determined to be noncompetitive inhibition, with the K i values equal to 1.340 μM, 1.151 μM and 1.829 μM, respectively. The inhibitory effect of M1-1 on CYP2B6 and CYP2D6 in HLMs, as well as the effect of M1-2 on CYP2C9 and CYP2D6 in HLMs, were determined to be competitive inhibition, with the K i values equal to 12.280 μM, 2.046 μM, 0.560 μM and 4.377 μM, respectively. The inhibitory effects of M1-1 on CYP2C9 in HLMs and M1-2 on Cyp2d1 in RLMs were determined to be mixed-type, with the K i values equal to 0.998 μM and 0.884 μM. The parameters could not be obtained due to the atypical kinetics of CYP2E1 in HLMs under the impact of M1-2., Conclusions: M1-1 and M1-2 exhibited inhibition for several CYP450 isozymes, especially CYP2B6, 2C9, 2D6 and 3A4/5. This observation may uncover potential drug-drug interactions and provide valuable insights for the clinical application of APA., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hu reports article publishing charges, equipment, drugs, or supplies, and writing assistance were provided by Guo-Xin., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Treatment-emergent sexual dysfunction is frequently reported by individuals with major depressive disorder (MDD) on antidepressants, which negatively impacts treatment adherence and efficacy. We investigated the association of polymorphisms in pharmacokinetic genes encoding cytochrome-P450 drug-metabolizing enzymes, CYP2C19 and CYP2D6 , and the transmembrane efflux pump, P-glycoprotein (i.e., ABCB1 ), on treatment-emergent changes in sexual function (SF) and sexual satisfaction (SS) in the Canadian Biomarker Integration Network in Depression 1 (CAN-BIND-1) sample., Methods: A total of 178 adults with MDD received treatment with escitalopram (ESC) from weeks 0-8 (Phase I). At week 8, nonresponders were augmented with aripiprazole (ARI) (i.e., ESC + ARI, n  = 91), while responders continued ESC (i.e., ESC-Only, n  = 80) from weeks 8-16 (Phase II). SF and SS were evaluated using the sex effects (SexFX) scale at weeks 0, 8, and 16. We assessed the primary outcomes, SF and SS change for weeks 0-8 and 8-16, using repeated measures mixed-effects models., Results: In ESC-Only, CYP2C19 intermediate metabolizer (IM) + poor metabolizers (PMs) showed treatment-related improvements in sexual arousal, a subdomain of SF, from weeks 8-16, relative to CYP2C19 normal metabolizers (NMs) who showed a decline, F (2,54) = 8.00, p  < 0.001, q  = 0.048. Specifically, CYP2C19 IM + PMs reported less difficulty with having and sustaining vaginal lubrication in females and erection in males, compared to NMs. Furthermore, ESC-Only females with higher concentrations of ESC metabolite, S-desmethylcitalopram (S-DCT), and S-DCT/ESC ratio in serum demonstrated more decline in SF ( r  = -0.42, p  = 0.004, q  = 0.034) and SS ( r  = -0.43, p  = 0.003, q  = 0.034), respectively, which was not observed in males. ESC-Only females also demonstrated a trend for a correlation between S-DCT and sexual arousal change in the same direction ( r  = -0.39, p  = 0.009, q  = 0.052)., Conclusions: CYP2C19 metabolizer phenotypes may be influencing changes in sexual arousal related to ESC monotherapy. Thus, preemptive genotyping of CYP2C19 may help to guide selection of treatment that circumvents selective serotonin reuptake inhibitor-related sexual dysfunction thereby improving outcomes for patients. Additionally, further research is warranted to clarify the role of S-DCT in the mechanisms underlying ESC-related changes in SF and SS. This CAN-BIND-1 study was registered on clinicaltrials.gov (Identifier: NCT01655706) on 27 July 2012.

Aims: Previously, retinoids have decreased CYP2D6 mRNA expression in vitro and induced CYP3A4 in vitro and in vivo. This study aimed to determine whether isotretinoin administration changes CYP2D6 and CYP3A activities in patients with severe acne., Methods: Thirty-three patients (22 females and 11 males, 23.5 ± 6.0 years old) expected to receive isotretinoin treatment completed the study. All participants were genotyped for CYP2D6 and CYP3A5. Participants received dextromethorphan (DM) 30 mg orally as a dual-probe substrate of CYP2D6 and CYP3A activity at two study timepoints: pre-isotretinoin treatment and with isotretinoin for at least 1 week. The concentrations of isotretinoin, DM and their metabolites were measured in 2-h postdose plasma samples and in cumulative 0-4-h urine collections using liquid chromatography-mass spectrometry., Results: In CYP2D6 extensive metabolizers, the urinary dextrorphan (DX)/DM metabolic ratio (MR) (CYP2D6 activity marker) was numerically, but not significantly, lower with isotretinoin administration compared to pre-isotretinoin (geometric mean ratio [GMR] [90% confidence interval (CI)] 0.78 [0.55, 1.11]). The urinary 3-hydroxymorphinan (3HM)/DX MR (CYP3A activity marker) was increased (GMR 1.18 [1.03, 1.35]) and the urinary DX-O-glucuronide/DX MR (proposed UGT2B marker) was increased (GMR 1.22 [1.06, 1.39]) with isotretinoin administration compared to pre-isotretinoin., Conclusions: Administration of isotretinoin did not significantly reduce CYP2D6 activity in extensive metabolizers, suggesting that the predicted downregulation of CYP2D6 based on in vitro data does not translate into humans. We observed a modest increase in CYP3A activity (predominantly CYP3A4) with isotretinoin treatment. The data also suggest that DX glucuronidation is increased following isotretinoin administration., (© 2023 British Pharmacological Society.)

Cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of up to 20% of small-molecule drugs and therefore, may impact the safety and efficacy of medicines in broad therapeutic areas. CYP2D6 is highly polymorphic, and the frequency of variants can differ across racial and ethnic populations, significantly affecting enzymatic function and drug metabolism. However, rare variants of CYP2D6 present a unique challenge for academia, industry, and regulatory agencies alike due to the lack of feasibility of characterizing their clinical relevance in clinical trials, particularly in variants that exhibit population-specific frequencies in racial and ethnic groups that are poorly represented in clinical trials. Despite significant advancement in pharmacogenomics, the substrate specificity and related clinical relevance of these CYP2D6 rare variants remain largely unclear, and further efforts are warranted to characterize the burden of these variants on adverse drug reactions and drug efficacy. Thus, cell-based in vitro systems can be used to inform substrate-specific effects and the overall relevance of a rare variant. Liver microsomes, cell-based expression systems, ex vivo primary samples, and purified variant protein have all been used with various substrates to potentially predict the clinical impact of new substrates. In this review, we identify rare variants of CYP2D6 that demonstrate differences across races in prevalence and thus are often unassessed in clinical trials. Accordingly, we examine current pharmacogenomic in vitro models used to analyze the functional impact of these rare variants in a substrate-specific manner. SIGNIFICANCE STATEMENT: Variants of CYP2D6 play a clinically relevant role in drug metabolism, leading to potential safety and efficacy concerns. Although the influence of prevalent variants is often well characterized, rare variants are traditionally not included in clinical trials. This review captures the clinical relevance of rare variants in CYP2D6 by highlighting in vitro models that analyze their impact on the metabolism of CYP2D6 substrates., (U.S. Government work not protected by U.S. copyright.)

CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary-derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4-OH-solanidine and 3,4-secosolanidine-3,4-dioic acid (SSDA) were determined using a sensitive liquid chromatography-mass spectrometry method in urine and in plasma at timepoints 0, 2.5, 5, 8, and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MRs) of metabolite to parent plasma concentrations were formed from single timepoints and the area under the curve (AUC). All participants were genotyped for CYP2D6. The intra-individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62% over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90%) but correlated significantly at all measured timepoints with AUC MR α-OH-metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any timepoint during the study day., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aim: The CYP2D6 gene is highly polymorphic, causing large interindividual variability in the metabolism of several clinically important drugs. Materials & methods: The authors investigated the diversity and distribution of CYP2D6 alleles in Indians using whole genome sequences (N = 1518). Functional consequences were assessed using pathogenicity scores and molecular dynamics simulations. Results: The analysis revealed population-specific CYP2D6 alleles ( *86 , *7 , *111 , *112 , *113 , *99 ) and remarkable differences in variant and phenotype frequencies with global populations. The authors observed that one in three Indians could benefit from a dose alteration for psychiatric drugs with accurate CYP2D6 phenotyping. Molecular dynamics simulations revealed large conformational fluctuations, confirming the predicted reduced function of *86 and *113 alleles. Conclusion: The findings emphasize the utility of comprehensive CYP2D6 profiling for aiding precision public health.

In the early stages of drug discovery, adequate evaluation of the potential drug-drug interactions (DDIs) of drug candidates is important. Several CYP3A activators are known to lead to underestimation of DDIs. These compounds affect midazolam 1'-hydroxylation but not midazolam 4-hydroxylation.We used both metabolic reactions of midazolam to evaluate the activation and inhibition of CYP3A activators simultaneously. For our CYP inhibition assay using cocktail probe substrates, simultaneous liquid chromatography-tandem mass spectrometry monitoring of 1'-hydroxymidazolam and 4-hydroxymidazolam for CYP3A was established in addition to monitoring of 4-hydroxydiclofenac and 1'-hydroxybufuralol for CYP2C9 and CYP2D6.The results of our cocktail inhibition assay were well correlated with those of a single inhibition assay, as were the estimated inhibition parameters for typical CYP3A inhibitors. In our assay, a proprietary compound that activated midazolam 1'-hydroxylation and tended to inhibit 4-hydroxylation was evaluated along with known CYP3A activators. All compounds were well characterised by comparison of the results of midazolam 1'- and 4-hydroxylation.In conclusion, our CYP cocktail inhibition assay can detect CYP3A activation and assess the direct and time-dependent inhibition potentials for CYP3A, CYP2C9, and CYP2D6. This method is expected to be very efficient in the early stages of drug discovery.

Background: Risperidone and, to a lesser extent, paliperidone are metabolized by CYP2D6; however, there are limited data related to variation in CYP2D6 phenotypes and the tolerability of these medications in children and adolescents. Furthermore, the impact of CYP2D6 on the association of risperidone and paliperidone with hyperprolactinemia in youth is not well understood. Methods: A retrospective chart review was performed in psychiatrically hospitalized children and adolescents prescribed risperidone ( n  = 263, age = 3-18 years, mean age = 13 ± 3 years, 49% female) or paliperidone ( n  = 124, age = 5-18 years, mean age = 15 ± 2 years, 44% female) who had CYP2D6 genotyping performed as part of routine care. CYP2D6 phenotypes were determined based on Clinical Pharmacogenetics Implementation Consortium guidelines and CYP2D6 inhibitors causing phenoconversion. Adverse effects were obtained from a review of the electronic health record, and patients were selected, in part, to enrich non-normal metabolizers. Results: Among risperidone-treated patients, 45% experienced an adverse effect, whereas 36% of paliperidone-treated patients experienced adverse effects. Discontinuation of risperidone due to lack of efficacy was more frequent in the CYP2D6 normal metabolizers and ultrarapid metabolizers compared with intermediate metabolizers (IMs) and phenoconverted poor metabolizers (pPMs) (54.5% vs. 32.7%, p  < 0.001). Discontinuation due to weight gain was more common among risperidone- than paliperidone-treated patients (17% vs. 7%, p  = 0.011). Among those taking paliperidone, CYP2D6 was associated with discontinuation due to side effects ( p  = 0.008), and youth with slower CYP2D6 metabolism (i.e., pPMs and IMs) were more likely to discontinue. Hyperprolactinemia was found in 10% of paliperidone-treated patients and 5% of risperidone-treated patients, and slower CYP2D6 metabolizers required higher risperidone doses to cause hyperprolactinemia ( p  = 0.011). Conclusions: CYP2D6 phenotype is associated with discontinuation of risperidone due to lack of efficacy and the dose of risperidone that induced hyperprolactinemia, as well as discontinuation of paliperidone due to adverse effects. Future studies should evaluate exposure-response and toxicity relationships in risperidone- and paliperidone-treated youth.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes ( CYP2C19 or CYP2D6 ), the serotonin transporter ( SLC6A4 ), and the serotonin receptor 2A subtype ( HTR2A ). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC 0-24 ; p  = 0.025), trough concentrations (C trough ; p  = 0.013), and elimination half-lives (t 1/2 ; p  < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia ( p  = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores ( p  = 0.017). Escitalopram maximum concentration, AUC 0-24 , CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.

Phellopterin (PLP) is a linear furanocoumarin widely found in citrus fruits and herbal medicines. The study aims to comprehensively investigate the mechanism of inhibition of CYP2D6 enzyme activity by PLP and its alteration of metoprolol pharmacokinetics. PLP was found to irreversibly inhibit CYP2D6 in time-, concentration-, and nicotinamide adenine dinucleotide phosphate-dependent manners. Coincubation with quinidine, which is a competitive inhibitor of CYP2D6, attenuated this time-dependent inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse the PLP-induced CYP2D6 inactivation. GSH trapping experiments provided strong evidence that PLP metabolic activation produces epoxide or γ-ketoaldehyde intermediates. In addition, pretreatment with PLP resulted in significant increases in C max and area under curve of plasma metoprolol in rats.

Introduction: Response to medications can differ widely among individual patients. Adverse drug reactions can lead to serious morbidity and mortality. Pharmacogenetic (PGx) testing can predict responses to medications and increased risks of adverse events where the genetic basis is understood. Several published manuscripts suggest positive impacts of systematic preemptive PGx testing. However, few studies have been conducted on PGx implementation in the Military Health System (MHS)., Material and Methods: A cross-sectional study of adult beneficiaries in a primary care clinic at a large military treatment facility was conducted in 2022. Participants underwent PGx genotyping of CYP2C19 and CYP2D6 genes at the Defense Health Agency Genetics Reference Laboratory. Participant medication lists were compared to the current Clinical Pharmacogenetic Implementation Consortium (CPIC) PGx gene-drug guidelines to assess potential actionability of these results., Results: Genotyping of CYP2C19 and CYP2D6 in 165 MHS beneficiaries (mean age: 65 years) revealed that 81.2% of participants had at least one abnormal PGx finding. Among those with an abnormal PGx result, 65% were taking a medication listed on the CPIC website with an association with the particular gene in which the finding was identified. In addition, 78% of all of the participants in the study were taking at least one medication that is metabolized by CYP2C19 or CYP2D6 with associated CPIC guidelines., Conclusions: Pharmacogenetic testing for CYP2C19 and CYP2D6 identified a substantial proportion of MHS patients at a single center who could benefit from evaluation of current medication regimens based on the CPIC guidelines. Individualized medical management may be warranted to a greater degree than previously recognized based on the findings given possible differences in medication metabolism. Many MHS beneficiaries already take medications metabolized by CYP2C19 and CYP2D6, and a substantial proportion may be at risk for preventable adverse events for medications metabolized by these enzymes. While preliminary, a large number of actionable polymorphisms among a relatively small set of individuals taking at-risk medications suggest that implementing PGx testing in clinical practice may be beneficial in the MHS with appropriate clinical infrastructure., (© The Association of Military Surgeons of the United States 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objective: A high rate of interindividual variability in response to tamoxifen (TAM) in breast cancer patients with CYP2D6 polymorphism has been reported, which affects the patient's therapeutic outcome. The objective of this study was to investigate the pharmacogenomics of CYP2D6 genotyping in Iranian patients with breast cancer treated with adjuvant TAM., Methods: A peripheral blood sample was obtained to determine the steady-state plasma concentrations of TAM and its metabolites (Endoxifen (EN) and 4-Hydroxytamoxifen (4-OHT)) using high-performance liquid chromatography with fluorescence detection (HPLC-FLU) assay. We detected CYP2D6 * 3, * 4, * 10, and * 17 single nucleotide polymorphisms via polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method., Results: A total of 84 Iranian estrogen receptor‑positive breast cancer patients receiving the daily dose of 20 mg tamoxifen were recruited. Although a consequent decrease in the median EN and 4-OHT concentrations was observed by comparing poor or intermediate metabolizer patients with an extensive metabolizer population, this difference did not reach a significant level. The mean plasma EN concentrations in poor and intermediate metabolizers were 46.1% (95% CI, 7.4-27.8%) and 59.4% (95% CI, 11.9-37.3%) of extensive metabolizer subjects, respectively. Poor and intermediate metabolizers had the mean plasma 4-OHT concentrations that were 46.6% (95% CI, 0.9-61.7%) and 73.2% (95% CI, 2.7-93.1%) of those of subjects who were extensive metabolizer, respectively., Conclusions: The possible role of genotyping in Iranian patients' response to treatment may explain inter-individual differences in the plasma concentrations of active metabolites of TAM., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Amirhossein sahebkar reports financial support was provided by Mazandaran University of Medical Sciences. The authors wish to thank the staff and the patients of Tooba clinic, Mazandaran, Sari, Iran., (Copyright © 2023. Published by Elsevier B.V.)

Cytochrome P450 2D6 (CYP2D6) is a critical hepatic drug-metabolizing enzyme in humans, responsible for metabolizing approximately 20%-25% of commonly used medications such as codeine, desipramine, fluvoxamine, paroxetine, and tamoxifen. The CYP2D6 gene is highly polymorphic, resulting in substantial interindividual variability in its catalytic function and the pharmacokinetics and therapeutic outcomes of its substrate drugs. Although many functional CYP2D6 variants have been discovered and validated, a significant portion of the variability in the expression and activity of CYP2D6 remains unexplained. In this study, we performed a genome-wide association study (GWAS) to identify novel variants associated with CYP2D6 protein expression in individual human livers, followed by a conditional analysis to control for the effect of functional CYP2D6 star alleles. We also examined their impact on hepatic CYP2D6 activity. Genotyping on a genome-wide scale was achieved using the Illumina Multi-Ethnic Genotyping Array (MEGA). A data-independent acquisition (DIA)-based proteomics method was used to quantify CYP2D6 protein concentrations. CYP2D6 activity was determined by measuring the dextromethorphan O-demethylation in individual human liver s9 fractions. The GWAS identified 44 single nuclear polymorphisms (SNPs) that are significantly associated with CYP2D6 protein expressions with a P value threshold of 5.0 × 10 -7 After the conditional analysis, five SNPs, including the cis-variants rs1807493 and rs1062753 and the trans-variants rs4073010, rs729559, and rs80274432, emerged as independent variants significantly correlated with hepatic CYP2D6 protein expressions. Notably, four of these SNPs, except for rs80274432, also exhibited a significant association with CYP2D6 activities in human livers, suggesting their potential as novel and independent cis- and trans-variants regulating CYP2D6. SIGNIFICANT STATEMENT: Using individual human livers, we identified four novel cis- and trans-pQTLs/aQTLs (protein quantitative trait loci/activity quantitative trait loci) of Cytochrome P450 2D6 (CYP2D6) that are independent from known functional CYP2D6 star alleles. This study connects the CYP2D6 gene expression and activity, enhancing our understanding of the genetic variants associated with CYP2D6 protein expression and activity, potentially advancing our insight into the interindividual variability in CYP2D6 substrate medication response., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

CYP2D6 variants contain various single nucleotide polymorphisms as well as differing levels of metabolic activity. Among these, one of the less active variants CYP2D6*10 (100C > T) is the most prevalent mutation in East Asians, including Japanese. This mutation leads to an amino acid substitution from proline to serine, which reduces the stability of CYP2D6 and consequently decreases its metabolic activity. In this study, we used a genome editing technology called the Precise Integration into Target Chromosome (PITCh) system to stably express six drug-metabolizing enzymes (CYP3A4, POR, uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), CYP1A2, CYP2C19, CYP2C9, and CYP2D6*10) in HepG2 (CYP2D6*10 KI-HepG2) cells to examine the effect of CYP2D6*10 on drug metabolism prediction. The protein expression levels of CYP2D6 in CYP2D6*10 KI-HepG2 cells were reduced relative to those in the CYP3A4-POR-UGT1A1-CYP1A2-CYP2C19-CYP2C9-CYP2D6 knock-in-HepG2 (CYPs-UGT1A1 KI-HepG2) cells. Consistent with the CYP2D6 protein expression results, CYP2D6 metabolic activity in CYP2D6*10 KI-HepG2 cells was reduced relative to CYPs-UGT1A1 KI-HepG2 cells. We successfully generated CYP2D6*10 KI-HepG2 cells with highly expressed, functional CYP2D6*10, as well as CYP1A2, 2C9, 2C19 and 3A4. CYP2D6*10 KI-HepG2 cells could be an invaluable model for hepatic metabolism and hepatotoxicity studies in East Asians, including Japanese.

My research focused on the effects of various drugs on (1) dopamine formation from p-tyramine catalyzed by polymorphic cytochrome P450 (CYP or P450) 2D6 variants and (2) endogenous steroid hormone hydroxylation catalyzed by CYP3A subfamily members (CYP3A4, CYP3A5, CYP3A7). The activation (cooperativity) of metabolic reactions catalyzed by P450s was especially emphasized. The effects of various psychotropic agents on dopamine formation from p-tyramine, catalyzed by wild-type CYP2D6.1 and CYP2D6 variants, including CYP2D6.2 (Arg296Cys;Ser486Thr), CYP2D6.10 (Pro34Ser;Ser486Thr), and CYP2D6.39 (Ser486Thr) were compared. Michaelis (K m ) and inhibition (K i ) constants of the psychotropic agents in the presence of CYP2D6.10 were higher than those observed in the presence of other CYP2D6 variants. Fluvoxamine, fluoxetine, milnacipran, and haloperidol activated CYP2D6-catalyzed dopamine formation [decreasing the K m and/or increasing the maximal velocity (k cat )], and this activation was CYP2D6 variant-dependent. Regarding the CYP3A subfamily, the effects of various compounds including endogenous steroid hormones on the 6β-hydroxylation of steroid hormones, such as testosterone, progesterone, and cortisol, were determined; it was found that testosterone, dehydroepiandrosterone, and/or α-naphthoflavone activated 6β-hydroxylation of cortisol and/or progesterone, but the effects varied in the presence of different CYP3A subfamily members. Further studies are required to confirm the mechanisms and therapeutic relevance of these activation phenomena.