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Abstract: Purpose: To build a semi-physiologically based pharmacokinetic model describing the uptake, metabolism and efflux of paclitaxel and its metabolites and investigate the effect of hypothetical genetic polymorphisms causing reduced uptake, metabolism or efflux in the pathway by model simulation and sensitivity analysis. Methods: A previously described intracellular pharmacokinetic model was used as a starting point for model development. Kinetics for metabolism, transport, binding and systemic and output compartments were added to mimic a physiological model with hepatic elimination. Model parameters were calibrated using constraints postulated as ratios of concentrations and amounts of metabolites and drug in the systemic plasma and output compartments. The sensitivity in kinetic parameters was tested using dynamic sensitivity analysis. Results: Predicted plasma concentrations of drug and metabolites were in the range of what has been observed in clinical studies. Given the final model, plasma concentrations of paclitaxel seems to be relatively little affected by changes in metabolism or transport, while its main metabolite may be largely affected even by small changes. If metabolites prove to be clinically relevant, genetic polymorphisms may play an important role for individualizing paclitaxel treatment. [Copyright &y& Elsevier]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Febuxostat is a xanthine oxidase inhibitor approved for lowering serum urate levels in hyperuricaemic gout patients. It is extensively metabolized both by conjugation via uridine diphosphate glucuronosyltransferase enzymes and by oxidation via cytochrome P450 enzymes. WHAT THIS STUDY ADDS • Using rosiglitazone as a CYP2C8 substrate, we have demonstrated that febuxostat does not impede CYP2C8 metabolic activity, because febuxostat had no impact on rosiglitazone pharmacokinetic parameters. We therefore suggest that febuxostat can be safely co-administered with CYP2C8-metabolized drugs. AIMS To determine the effect of febuxostat on cytochrome P450 2C8 (CYP2C8) activity using rosiglitazone as a CYP2C8 substrate. METHODS Healthy subjects received febuxostat 120 mg daily (regimen A) or matching placebo (regimen B) for 9 days along with a single oral dose of rosiglitazone 4 mg on day 5 in a double-blind, randomized, cross-over fashion (≥7 day washout between periods). Plasma samples for analysis of the impact of febuxostat on the pharmacokinetics (PK) of rosiglitazone and its metabolite, N-desmethylrosiglitazone, were collected for 120 h after co-administration. RESULTS Of the 39 subjects enrolled, 36 completed the study and were included in the PK analyses. Rosiglitazone PK parameters were comparable between regimens A and B. Median time to maximal plasma concentration, mean maximal plasma concentration (Cmax), area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration (AUC0-tlqc), AUC from time zero to infinity (AUC0-∞), and terminal elimination half-life for regimen A were 0.50 h, 308.6 ng ml−1, 1594.9 ng h ml−1, 1616.0 ng h ml−1 and 4.1 h, respectively, and for regimen B they were 0.50 h, 327.6 ng ml−1, 1564.5 ng h ml−1, 1584.2 ng h ml−1 and 4.0 h, respectively. Point estimates for the ratio of regimen A to regimen B (90% confidence intervals) for rosiglitazone Cmax, AUC0-tlqc and AUC0-∞ central values were 0.94 (0.89-1.00), 1.02 (1.00-1.04) and 1.02 (1.00-1.04), respectively. CONCLUSIONS Co-administration of febuxostat had no effect on rosiglitazone or N-desmethylrosiglitazone PK parameters, suggesting that febuxostat can be given safely with drugs metabolized through CYP2C8. [ABSTRACT FROM AUTHOR]

The inhibitory effects of five flavonoids with distinct chemical classes (flavones [luteolin], flavonols [quercetin and quercitrin], and flavanones [hesperetin and hespiridin]) on cDNA-expressed CYP2C8 were investigated. CYP2C8 was co-expressed with NADPH-cytochrome P450 reductase in Escherichia coli and used to characterise potency and mechanism of these flavonoids on the isoform. Tolbutamide 4-methylhydroxylase, a high-performance liquid chromatography-based assay, was selected as marker activity for CYP2C8. Our results indicated that the flavonoids inhibited CYP2C8 with different potency. The order of inhibitory activities was quercetin > luteolin > hesperetin > hesperidin > quercitrin. All of these compounds however exhibited mechanism-based inhibition. A number of structural factors were found to be important for inhibition; these include the molecular shape (volume to surface ratio), the number of hydroxyl groups as well as glycosylation of the hydroxyl group. Quercetin was the most potent inhibitor among the flavonoids examined in this study, and our data suggest that it should be examined for potential pharmacokinetic drug interactions pertaining to CYP2C8 substrates in vivo. [ABSTRACT FROM AUTHOR]

Context: Artesunate (AS) and amodiaquine (AQ) are two prodrugs widely used as antimalarial agents and are metabolized by the CYP P450 2A6 (CYP 2A6) and CYP P450 2C8 (CYP 2C8) enzymes, respectively. Objective: In this study, we aim to investigate the association of both genes on AS and AQ's tolerabilities in the hope of identifying a pharmacogenetic approach that could be useful in prediction and prevention of adverse drug reactions (ADRs) among Malaysian population. Materials and methods: In this randomized crossover study, loose and AS/AQ formulations were administered to normal healthy volunteers ( n == 24) over two study phases. The drugs' tolerabilities (incidence of facial flushing, giddiness, headache, nausea, abdominal discomfort, progression of liver enzymes and neutrophil counts) were compared between the two treatment arms. Volunteers were also genotyped for the CYP2C8 and CYP2A6 variants. Results: The frequency of the CYP2A6**1B, CYP2A6**4, CYP2A6**8 and CYP2A6**9 alleles were 54.2%, 16.7%, 4.2% and 10.4%, respectively. No mutations for CYP2C8 gene were, however, detected. Most (96%) of the subjects were of the Malay ethnicity. Subjects having the CYP2A6**1B variants responsible for ultra rapid metabolism of AS suffered a significantly higher incidence of ADRs. Discussion: Our study is the first to report that CYP2A6 genotyping influences AS's ADR. Gender also plays a role where females reported more incidences of nausea ( p < 0.05). Conclusion: It is concluded that genetic polymorphisms of CYP2A6 as well as gender influence the side effect profiles of subjects receiving AS among this Malaysian population. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cytochrome P450 (CYP) 2C8 is the principal enzyme responsible for the metabolism of arachidonic acid and various drugs, and influences drug-drug interactions and some associated diseases. Large interindividual differences in CYP2C8 enzymatic activity and several nonsynonymous genetic variations have been reported in different races. Therefore, how to identify CYP2C8 polymorphisms efficiently for genotyping in different populations is very important. Methods: A high resolution melting (HRM) analysis was used to characterize the CYP2C8 polymorphism. Genomic DNA was extracted from peripheral blood samples from 95 normal individuals in Taiwan. Nine exons of the CYP2C8 gene were screened by HRM analysis. All results were confirmed by direct DNA sequencing. Results: Five new single nucleotide polymorphisms (SNPs) were found in this study; two SNPs [1189G>A (D397N) and 1230C>T (G410G)] were in exon 8 and the others [1312G>C (E438Q), 1497T>C (A499A) and 1677delT (559delL)] were in exon 9. The 1497T>C (A499A) was the most common variant with an allele frequency of 20.53% but without amino acid substitution. Conclusions: HRM analysis is a fast, reliable, accurate and cost-effective screening method for gene mutations, even very similar cDNA sequences with 83% identities, compared with CYP2C8 and CYP2C9. [Copyright &y& Elsevier]

Aim: To evaluate the impact of polymorphisms in the cytochrome P450 (CYP) 2C9, 2C19 and 2C8 genes on the risk of mild hypoglycaemic attacks in patients treated with sulphonylureas. Methods: One hundred and eight type 2 diabetic patients (50 men, 58 women), treated with oral antidiabetics, including at least one from the sulphonylurea group (glimepiride n = 50, gliclazide n = 46, or glipizide n = 12) for 3 months or longer, were included in the study. Symptoms of hypoglycaemia (sweating, tremor, anxiety and palpitations) during a 3 month period were recorded and confirmed by home glucose measurements. Gender, age, body mass index, creatinine clearance, HbA1c, oral antidiabetic dose and concomitant medication were assessed together with functional CYP2C9, CYP2C19 and CYP2C8 polymorphisms, analysed by real-time PCR methods. Results: Fifteen patients (eight men, seven women) reported hypoglycaemia symptoms which were validated by their home glucose measurements (< 70 mg/dl). Heterozygosity and homozygosity for CYP2C9 variant alleles ( *2 or *3) tended to be more frequent among patients who reported hypoglycaemic attacks (60 and 7%) than those who did not (39 and 3%). Similarly, the CYP2C8*1/*3 genotype tended to be more frequent in patients with (47%) than without (27%) hypoglycaemia, while no such trend was observed for CYP2C19 variants. However, only in the gliclazide group a significant association between CYP2C9 genotype and hypoglycaemic attacks was observed ( P = 0.035). None of the other covariates showed any significant association with the risk of hypoglycaemic attacks. Conclusions: CYP2C9 polymorphisms leading to decreased enzyme activity show a modest impact on the risk of mild hypoglycaemia attacks during oral antidiabetic treatment, with a significant association in patients treated with gliclazide. [ABSTRACT FROM AUTHOR]

Purpose: Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival. Methods: The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients' toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis. Results: Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival. Conclusion: CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin. [ABSTRACT FROM AUTHOR]

The cytochrome P450 (CYP) superfamily plays a key role in the oxidative metabolism of a wide range of drugs and exogenous chemicals. CYP2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel in the human liver. Nearly all previous works about polymorphic variants of CYP2C8 were focused on unpurified proteins, either cells or human liver microsomes; therefore their structure-function relationships were unclear. In this study, two polymorphic enzymes of CYP2C8 (CYP2C8.4 (I264M) and CYP2C8 P404A) were expressed in E. coli and purified. Metabolic activities of paclitaxel by the two purified polymorphic enzymes were observed. The activity of CYP2C8.4 was 25% and CYP2C8 P404A was 30% of that of WT CYP2C8, respectively. Their structure-function relationships were systematically investigated for the first time. Paclitaxel binding ability of CYP2C8.4 increased about two times while CYP2C8 P404A decreased about two times than that of WT CYP2C8. The two polymorphic mutant sites of I264 and P404, located far from active site and substrate binding sites, significantly affect heme and/or substrate binding. This study indicated that two important nonsubstrate recognition site (SRS) residues of CYP2C8 are closely related to heme binding and/or substrate binding. This discovery could be valuable for explaining clinically individual differences in the metabolism of drugs and provides instructed information for individualized medication. [ABSTRACT FROM AUTHOR]

Purpose: Gemfibrozil, a strong inhibitor of cytochrome P450 (CYP) 2C8 in vivo, was recently found to markedly increase the plasma concentrations of montelukast in humans. Like montelukast, zafirlukast is a substrate of CYP2C9 and CYP3A4 and a potent inhibitor of CYP2C8 in vitro. To investigate the contribution of CYP2C8 to the metabolism of zafirlukast in vivo, we studied the effect of gemfibrozil on the pharmacokinetics of zafirlukast. Methods: Ten healthy subjects in a randomized cross-over study took gemfibrozil 600 mg or placebo twice daily for 5 days, and on day 3, a single oral dose of 20 mg zafirlukast. The plasma concentrations of zafirlukast were measured for 72 h postdose. Results: The mean total area under the plasma concentration-time curve of zafirlukast during the gemfibrozil phase was 102% (geometric mean ratio; 95% confidence interval 89-116%) of that during the placebo phase. Furthermore, there were no statistically significant differences in the peak plasma concentration, time of peak concentration, or elimination half-life of zafirlukast between the phases. Conclusions: Gemfibrozil has no effect on the pharmacokinetics of zafirlukast, indicating that CYP2C8 does not play a significant role in the elimination of zafirlukast. [ABSTRACT FROM AUTHOR]

Cytochrome P-450 (CYP)-derived epoxyei-cosatrienoic acids (EETs) possess potent anti-inflammatory effects in vitro. However, the effect of increased CYP-mediated EET biosynthesis and decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on vascular inflammation in vivo has not been rigorously investigated. Consequently, we characterized acute vascular inflammatory responses to endotoxin in transgenic mice with endothelial expression of the human CYP2J2 and CYP2C8 epoxygenases and mice with targeted disruption of Ephx2. Compared to wild-type controls, CYP2J2 transgenic, CYP2C8 transgenic, and Ephx2−/− mice each exhibited a significant attenuation of endotoxin-induced activation of nuclear factor (NF)-κB signaling, cellular adhesion molecule, chemokine and cytokine expression, and neutrophil infiltration in lung in vivo. Furthermore, attenuation of endotoxin-induced NF-κB activation and cellular adhesion molecule and chemokine expression was observed in primary pulmonary endothelial cells isolated from CYP2J2 and CYP2C8 transgenic mice. This attenuationwas inhibited bya putative EET receptor antagonist and CYP epoxygenase inhibitor, directly implicating CYP epoxygenase-derived EETs with the observed anti-inflammatory phenotype. Collectively, these data demonstrate that potentiation of the CYP epoxygenase pathway by either increased endothelial EET biosynthesis or globally decreased EET hydrolysis attenuates NF-κB-dependent vascular inflammatory responses in vivo and may serve as a viable anti-inflammatory therapeutic strategy.—Deng, Y., Edin, M. L., Theken, K N., Schuck, R N., Flake, G. P., Kannon, M. A., DeGraff, L. M., Lih, F. B., Foley, J., Bradbury, J. A., Graves, J. P., Tomer, K. B., Falck, J. R., Zeldin, D. C., Lee, C. R. Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice. FASEB J. 25, 703–713 (2011). [ABSTRACT FROM AUTHOR]

Taxanes represent a group of anticancer drugs with a wide range of activity against breast cancer. Therapy side effects include haematologic toxicity (neutropenia, leucopenia), peripheral neuropathy and hypersensitivity, and demonstrate inter-individual variations. Since it is known that three genes are implicated in Taxane turnover, namely ABCB1 in the transport, CYP2C8 in the metabolism and CYP1B1 in the activity, we explored the association among polymorphisms (single nucleotide polymorphisms, SNPs) in these three genes and the occurrence of Taxane-induced toxicity. We studied 95 patients affected by breast cancer and under treatment with Taxanes as adjuvant, metastatic or neo-adjuvant therapy. We genotyped them for SNPs in the CYP2C8 (alleles *1, *2, *3 and *4), CYP1B1 (alleles *1 and *3) and ABCB1 (1236 C>T; 2677 G>T/A; 3435 C>T) genes by real-time PCR assay. We observed a significant association between the CYP1B1*3 allele and a lower occurrence of hypersensitivity reactions to Taxane treatment. We speculate that the highest production of 4-hydroxyestradiol (4-OHE2) metabolite by CYP1B1*3 allele could increase the formation of the 4-OHE2-Taxane adduct and possibly inhibit Taxane toxicity. We suggest that CYP1B1 might affect Taxane hypersensitivity therefore representing, if confirmed in a large cohort of patients, an exploratory hypersensitivity predictive biomarker. [ABSTRACT FROM AUTHOR]

Renal cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) regulate sodium transport and blood pressure. Although endothelial CYP-derived EETs are potent vasodilators, their contribution to the regulation of blood pressure remains unclear. Consequently, we developed transgenic mice with endothelial expression of the human CYP2J2 and CYP2C8 epoxygenases to increase endothelial EET biosynthesis. Compared to wild-type littermate controls, an attenuated afferent arteriole constrictor response to endothelin-1 and enhanced dilator response to acetylcholine was observed in CYP2J2 and CYP2C8 transgenic mice. CYP2J2 and CYP2C8 transgenic mice demonstrated modestly, but not significantly, lower mean arterial pressure under basal conditions compared to wild-type controls. However, mean arterial pressure was significantly lower in both CYP2J2 and CYP2C8 transgenic mice during coadministration of N-nitro-L-arginine methyl ester and indomethacin. In a separate experiment, a high-salt diet and subcutaneous angiotensin II was administered over 4 wk. The angiotensin/high-saltinduced increase in systolic blood pressure, proteinuria, and glomerular injury was significantly attenuated in CYP2J2 and CYP2C8 transgenic mice compared to wild-type controls. Collectively, these data demonstrate that increased endothelial CYP epoxygenase expression attenuates afferent arteriolar constrictor reactivity and hypertension-induced increases in blood pressure and renal injury in mice. We conclude that endothelial CYP epoxygenase function contributes to the regulation of blood pressure. [ABSTRACT FROM AUTHOR]

The cytochrome P450 (CYP) superfamily plays a key role in the oxidative metabolism of a wide range of exogenous chemicals. CYP2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel in the human liver, and carries out the oxidative metabolism of at least 5% of clinical drugs. Polymorphisms in CYP2C8 have been closely implicated in individualized medication. CYP2C8.3, a common polymorph of CYP2C8 with dual amino acid substitutions R139K and K399R, is found primarily in Caucasians. In this study, CYP2C8.3 and its wild type (WT) CYP2C8 were expressed in E. coli, and their purified proteins were characterized by UV-visible spectroscopy, mass spectrometry, and circular dichroism. Their thermal stability, substrate binding ability, and metabolic activity against paclitaxel were investigated. The electron transfer kinetics during paclitaxel metabolism by WT CYP2C8 or CYP2C8.3 was studied by stopped-flow kinetics. The results revealed that mutations in CYP2C8.3 did not greatly influence the heme active site or protein thermal stability and paclitaxel binding ability, but the metabolic activity against paclitaxel was significantly depressed to just 11% of that of WT CYP2C8. Electron transfer from CYP reductase to CYP2C8.3 was found to be significantly slower than that to WT CYP2C8 during catalysis, and this might be the main reason for the depressed metabolic activity. Since the polymorph CYP2C8.3 is defective in catalyzing substrates of CYP2C8 in vitro, it might be expected to have important clinical and pathophysiological consequences in homozygous individuals, and this study provides valuable information in this aspect. [ABSTRACT FROM AUTHOR]

Background: Oleic acid is a major systemically circulating fatty acid in humans with atheroprotective and immunomodulatory properties. As of today, the contribution of individual cytochrome P450 (CYP) mono-oxygenases to the epoxidation of this fatty acid is unknown. Furthermore, the extent of the oleic acid oxidation product cis-9,10-epoxyoctadecanoic acid ( cis-EODA) in humans and its plasma levels in patients with impaired liver function are not known. Patients and methods: We studied cis-EODA in plasma of patients suffering from chronic liver diseases, a condition that often displays impaired liver CYP enzyme activities. Fifteen CYP mono-oxygenases were investigated in vitro as a potential source of cis-EODA. Results: Strikingly, plasma levels of cis-EODA were significantly repressed ( P<0.0005) when patients with liver impairment ( n=16) were compared with healthy subjects ( n=14). Production of cis-EODA was catalysed by CYP in the following order: 2C8, 2C9, 2C19, 3A4, 1A2 and CYP3A7. Conclusion: cis-EODA plasma concentrations are decreased in hepatic disease with impaired liver function. Oleic acid is primarily oxidized to oleic acid oxide ( cis-EODA) by CYP2C and CYP3A mono-oxygenases. The liver is the major organ responsible for the oxidation of oleic acid to cis-EODA, and thus, cis-EODA may be a suitable biomarker to assess liver function. [ABSTRACT FROM AUTHOR]

1. To analyze the polymorphic activities of CYP2C8 and evaluate their impact on drug inhibitory potential, three CYP2C8 allelic variants (CYP2C8.2, CYP2C8.3, and CYP2C8.4), two non-synonymous single nucleotide polymorphic variants (R139K and K399R, carried by CYP2C8.3), and wild-type CYP2C8 (CYP2C8.1) were heterologously expressed in yeast, and their enzymatic activities were characterized. CYP2C8 inhibition-based in vitro and in vivo drug-drug interactions (DDIs) in wild-type and variant CYP2C8s were then predicted. 2. Functional characterization of five CYP2C8 variants revealed similar enzymatic activity in R139K and low activity in CYP2C8.2, CYP2C8.3, CYP2C8.4, and K399R compared with CYP2C8.1. The systematic analysis of these CYP2C8 variants can provide more homogeneous data for predicting CYP2C8 phenotypes and could be applied to personalized drug therapy. 3. Prediction of DDIs indicated that CYP2C8.4, R139K, and K399R dramatically alter the IC50 values of nifedipine, troglitazone, and raloxifene, and R139K qualitatively and quantitatively reduces the risk of in vivo paclitaxel-raloxifene and paclitaxel-troglitazone interactions. The results provide the first evidence that CYP2C8 inhibition-based DDIs may be influenced by CYP2C8 genetic polymorphisms. These inhibition data can be used by pharmacologists in the design of in vivo studies to further assess and address the potential role of CYP2C8 genotype-dependent inhibition in clinical DDIs. [ABSTRACT FROM AUTHOR]

Epoxyeicosatrienoic acids (EETs) are important mediators in vasodilatation, acting as endothelium-derived hyperpolarizing factors. CYP2C enzymes catalyze the metabolism of arachidonic acid to EETs. Genetic variation within the genes encoding for these enzymes may result in differences in vascular response, among others in myocardial tissue, and may therefore increase the risk of myocardial infarction (MI). CYP2C8 and CYP2C9 are encoded by the genes of the same name. CYP2C9 polymorphisms have been associated with an increased risk of MI. As CYP2C8 is genetically linked to CYP2C9 and on account of its role in EET production, we hypothesized that CYP2C8 polymorphisms are associated with the risk of MI.This study was embedded within the Rotterdam study, a prospective population-based cohort study. The study population included all participants with successful genotyping and without prevalent MI (n=5199). Twenty-five tagging single nucleotide polymorphisms within and around the gene-coding areas of CYP2C8 and CYP2C9 were tested for an association with incident MI using survival analysis techniques with multivariable adjustment for potential confounders.During follow-up, 290 persons developed an incident MI. One tag-SNP in the CYP2C8 gene was associated with incident MI after Bonferroni correction, rs1058932C>T (variant genotype hazard ratio 1.54; 95% CI: 1.22-1.95). There was a significant gene-sex interaction with a relative excess risk of 1.40 (95% CI: 0.33-2.47) for men.SNP rs1058932C>T within the CYP2C8 gene is associated with an increased risk of MI, which is, possibly because of a vascular effect of sex steroids, highest in males. [ABSTRACT FROM AUTHOR]

Aim: To investigate the effects of CYP3A4 and CYP2C8 enzymes on repaglinide’s pharmacokinetics in healthy Malaysian subjects. Methods: Subjects (n = 121) received oral repaglinide (4 mg). Blood samples were taken at 0, 30, 60, 120, 180 and 240 min and serum concentrations of repaglinide were determined using high-performance liquid chromatography. Subjects were also genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for CYP3A4*4, *5 and*18 and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles. Results: The allele frequencies of CYP2C8*1, *2, *3, *4 and *5 were 95.04, 0.40, 0.40, 0 and 4.13%, respectively. The frequencies of the CYP3A4*1, *4, *5 and *18 alleles were 97.93, 0, 0 and 2.07%, respectively. CYP2C8 and CYP3A4 genotypes were not significantly associated with repaglinide’s blood glucose-lowering effect. However, the CYP3A4 genotype significantly influenced some of repaglinide’s pharmacokinetics, where the mean elimination rate constant was 44.0% lower (p = 0.04) and the mean half-life was 33.8% higher (p = 0.04) in subjects with the CYP3A4*1/*18 genotype as compared to those with the normal CYP3A4*1/*1 genotype. This result confirms that CYP3A4 plays a large role in metabolizing repaglinide. Conclusion: Genetic polymorphisms of CYP3A4, specifically CYP3A4*18, play a major role in contributing to the interindividual variability in repaglinide’s pharmacokinetics. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim The aim of the present case report was to describe a novel pharmacokinetic drug-drug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel. Methods The patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl-β-D-glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6α-hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry. Results The patient was a 60-year-old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238 l h−1, which was only 62% of the cohort geometric mean (385 l h−1; range 176-726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30-min preincubation with 100 μM clopidogrel acyl-β-D-glucuronide inhibited the depletion rate of 0.5 μM paclitaxel by 51% and the formation rate of 6α-hydroxypaclitaxel by 77%. Conclusion This is the first report of a clopidogrel-paclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)-mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided. [ABSTRACT FROM AUTHOR]

Background: CYP2C8/9 polymorphisms may influence breast cancer-free survival after diagnosis due to their role in the metabolism of tamoxifen, paclitaxel, and other chemotherapy. cytochrome P450 (CYP)2C8/9 metabolise arachidonic acid to epoxyeicosatrienoic acids, which enhance migration and invasion in vitro and promote angiogenesis in vivo. We aimed to investigate the frequency of CYP2C8/9 polymorphisms in relation to breast tumour characteristics and disease-free survival.Methods: A prospective series of 652 breast cancer patients from southern Sweden was genotyped for CYP2C8*3, CYP2C8*4, CYP2C9*2, and CYP2C9*3. Blood samples and questionnaires were obtained pre- and postoperatively. Clinical information and tumour characteristics were obtained from patients' charts and pathology reports.Results: Frequencies of CYP2C8/9 polymorphisms were similar to healthy European populations. Significantly less node involvement (P=0.002) and fewer PR+ tumours (P=0.012) were associated with CYP2C8*4. Median follow-up was 25 months and 52 breast cancer-related events were reported. In a multivariate model, CYP2C8/9*3/*1*/*2/*1 was the only factor associated with increased risk for early events in 297 tamoxifen-treated, ER-positive patients, adjusted HR 2.54 (95%CI 1.11-5.79). The effect appeared to be driven by CYP2C8*3, adjusted HR 8.56 (95%CI 1.53-51.1).Conclusion: Polymorphic variants of CYP2C8/9 may influence breast tumour characteristics and disease-free survival in tamoxifen-treated patients. [ABSTRACT FROM AUTHOR]

We have studied the global frequency distributions of 10 single nucleotide polymorphisms (SNPs) across 132 kb of CYP2C8 and CYP2C9 in ∼2500 individuals representing 45 populations. Five of the SNPs were in noncoding sequences; the other five involved the more common missense variants (four in CYP2C8, one in CYP2C9) that change amino acids in the gene products. One haplotype containing two CYP2C8 coding variants and one CYP2C9 coding variant reaches an average frequency of 10% in Europe; a set of haplotypes with a different CYP2C8 coding variant reaches 17% in Africa. In both cases these haplotypes are found in other regions of the world at <1%. This considerable geographic variation in haplotype frequencies impacts the interpretation of CYP2C8/CYP2C9 association studies, and has pharmacogenomic implications for drug interactions.The Pharmacogenomics Journal (2009) 9, 283–290; doi:10.1038/tpj.2009.10; published online 21 April 2009 [ABSTRACT FROM AUTHOR]

Since the late 1980s, chemotherapy-induced cognitive impairment, also known as “chemobrain”, has been a recognized side effect in patients undergoing cancer treatment (Matsuda et al., 2005). Although products containing Ginkgo biloba may be used by patients undergoing chemotherapy with paclitaxel and other agents, the potential for an herb-drug interaction with this combination has not been adequately explored. This report describes the inhibition of paclitaxel metabolism by Ginkgo preparations in vitro in human hepatocytes. Hydrolyzate of Ginkgo extract (10-100 mM in terpene lactone concentration) caused a dose-dependent inhibition of the 6α -hydroxylation of paclitaxel, the enzymatic activity responsible for the majority of the clearance of that drug in clinical applications; parent extract had no effect. Contrary to the assumed therapeutic benefit of Ginkgo, its concomitant use with paclitaxel could result in elevated blood levels of the chemotherapeutic, with attendant exacerbation of cognitive impairment and other toxic effects associated with cancer therapy. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a chronic infectious disease which remains a main cause of death worldwide, and arises more and more concerns in recent years. CytochromeP450 (CYP450) is involved in the metabolism of many exogenous and endogenous compounds, and its polymorphism is associated with many diseases. The objective of our study was to explore the relationship between CYP450 polymorphisms and TB susceptibility in Northwest Chinese Han population. 506 TB patients and 506 controls were recruited for our study, and their DNA were extracted. Six single nucleotide polymorphisms (SNPs) were selected for genotype. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated to evaluate the correlation between SNPs and TB risk. The genotype "TA" of CYP2C8 rs2275620 was related to an increased risk of TB in the co-dominant model (OR = 1.33, 95%CI =1.00–1.76, p = 0.049). In females, CYP2E1 rs2070672 was related to an increased TB susceptibility (co-dominant: OR = 1.62, 95%CI = 1.04–2.52, p = 0.032; dominant: OR = 1.66, 95%CI = 1.08–2.56, p = 0.020; additive: OR = 1.60, 95%CI = 1.08–2.36, p = 0.018), and CYP2E1 rs2515641 was also associated with an increased risk of TB (co-dominant: OR = 1.90, 95%CI = 1.19–3.04, p = 0.007; dominant: OR = 1.94, 95%CI = 1.23–3.05, p = 0.004; additive: OR = 1.80, 95%CI = 1.20–2.71, p = 0.005) in women. But there was no statistical significance between haplotypes and TB risk (p > 0.05). Our research showed CYP2C8 and CYP2E1 polymorphisms are associated with an increased risk of TB in Northwest Chinese Han population, which may provide a crucial help on defining new therapeutic strategies for chemoprevention. • A case-control study explored the relationship between CYP2C8 and CYP2E1 polymorphisms with TB risk in Northwest Chinese Han population. • Genotype "TA" of CYP2C8 rs2275620 is related to an increased risk of TB. • In females, CYP2E1 rs2070672 and rs2515641 are associated with an increased risk of TB. [ABSTRACT FROM AUTHOR]

The calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus (Tac) help prevent allograft rejection but are associated with nephrotoxicity. Cytochrome P450 2C8 (CYP2C8) and CYP2J2 are polymorphic enzymes expressed in the kidney that metabolize arachidonic acid (AA) to epoxyeicosatrienoic acids, promoting kidney homeostasis. This study examined the association between CNI-induced nephrotoxicity in liver transplant patients and CYP2C8 and CYP2J2 polymorphisms.Liver transplantation patients receiving CNIs for at least 3 years were genotyped for CYP2C8∗3, CYP2C8∗4, CYP2C8 Haplotypes B and C, and CYP2J2∗7 and evaluated for nephrotoxicity (serum creatinine ≥1.6 mg/dl) 3-year post-transplantation. CYP2C8 proteins were also engineered in E. coli and their activity towards AA and inhibition by CNIs was investigated in vitro.The risk of kidney disease post-transplantation was positively associated with CYP2C8∗3 genotype. Odds ratios for all participants carrying at least one CYP2C8∗3 allele were significant [odds ratio=2.38 (1.19-4.78)]. Stratification by CNI indicated a significant association between CYP2C8∗3 and nephrotoxicity among patients receiving Tac but not CsA. The risk of renal dysfunction was not significantly influenced by CYP2C8∗4, CYP2J2∗7, or CYP2C8 haplotype B genotypes although inheritance of haplotype C seems to be protective. In vitro, the gene products of CYP2C8∗3 and CYP2C8∗4 were deficient in AA epoxidation, retaining 26 and 18% of wild-type activity, respectively. Circulating plasma concentrations of CsA and Tac inhibited CYP2C8 wild-type in vitro epoxidation of AA by 17 and 35%, respectively.Inheritance of CYP2C8∗3 is associated with a higher risk of developing renal toxicity in patients treated chronically with CNIs, and especially Tac, possibly by reducing formation of kidney protecting vasodilatory epoxyeicosatrienoic acids. [ABSTRACT FROM AUTHOR]

Some of the largest therapeutic drug exposures in the planet involve drugs employed against malaria and TB, two main global infectious diseases. Amodiaquine for malaria and isoniazid for TB are two pivotal drugs in the management of these diseases. Both drugs have been associated with severe adverse events. Amodiaquine and isoniazid are metabolized polymorphically by CYP2C8 and N-acetyltransferase 2, respectively. The polymorphic genes coding for these enzymes presently represent the best candidates for the application of personal pharmacogenetics for these diseases. We review the main reasons for this view, while asking the pivotal question of whether it is presently possible for pharmacogenetic-based personalized medicine to be applied in the malaria and TB settings of the Developing World. [ABSTRACT FROM AUTHOR]

CYP2C8 seems to be involved in diclofenac 5-hydroxylation, while, in vitro, the 4′-hydroxylation and 3′-hydroxylation seem to be mediated mainly by CYP2C9. We have demonstrated the relevance of CYP2C9 genotypes for diclofenac 4′-hydroxylation in healthy volunteers, so that the present study was aimed at analyzing the role of both CYP2C8 and CYP2C9 genotypes on diclofenac metabolism, as well as determining the CYP2C8 allele frequencies and their relationship with CYP2C9 variants. A group of 142 healthy white Spanish volunteers was studied. Previously, 102 of these subjects had been phenotyped with diclofenac and genotyped for CYP2C9. The CYP2C8 genotypes were determined by allele-specific PCR-RFLP methods. The urinary concentrations of diclofenac and its main metabolites were analysed using an HPLC-UV method after the administration of a single oral dose of diclofenac as described previously for part of the population studied here. The diclofenac/5-hydroxydiclofenac urinary concentration ratio was higher in individuals carrying a CYP2C8*3 or CYP2C8*4 allele than in those homozygous for wild-type allele CYP2C8*1 ( P < 0.05). Moreover, approximately 93% of the subjects with a CYP2C8*3 allele also carried a CYP2C9*2, and 80% of the subjects that had CYP2C9*2 variant also carried a CYP2C8*3. In addition, the four CYP2C9*2/*2 individuals were CYP2C8*3/*3. This is the first study showing the influence of CYP2C8 genotypes on diclofenac metabolism in vivo. The linkage disequilibrium between CYP2C8*3 and CYP2C9*2 alleles was confirmed in this Spanish population. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: (i) To define the incidence of alleles CYP2C8*1 to *5 in a Spanish population; (ii) to test the impact of such alleles, and those of CYP2C9, on the metabolism of racemic ibuprofen, R-ibuprofen and S-ibuprofen; and (iii) to discern whether those metabolic alterations have safety implications. Methods: Data from three phase I clinical trials with 69 healthy volunteers taken ibuprofen were analyzed. Genotyping were performed by PCR. Pharmacokinetic parameters were determined in studies 1 and 2 by non-compartmental analysis. Levels of COX-1, COX-2, eNOS and iNOS were determined by Western Blots in gastric biopsies of study 3. Results: Allelic frequencies were 0.80, 0.02, 0.11, 0.07 and 0 for CYP2C8*1, *2, *3, *4 and *5. CYP2C9*3 allele had a decreased racemic ibuprofen metabolism, leading to a 30% augmentation of AUC0−∞ and a 30% reduction of clearance compared to CYP2C9*1 (p <0.05). CYP2C8*3 had a 20% augmentation of clearance compared to CYP2C8*1 (p <0.05) of R-ibuprofen. CYP2C9*3 had a 45% reduction of clearance, as well as a 87% and 47% augmentation of AUC0−∞ and t 1/2 with respect to CYP2C9*1 of S-ibuprofen and a 30% reduction of clearance of R-ibuprofen. A decreased iNOS expression was found in CYP2C8*3 compared to wild type (p <0.05). Adverse events in CYP2C8*3 (20%) and *4 (20%) were fewer than in CYP2C8*1 (77%). Conclusions: This study suggest an impaired metabolism of racemic, S-ibuprofen and R-ibuprofen in CYP2C9*3; an increased R-ibuprofen metabolism in CYP2C8*3; and fewer adverse events in CYP2C8*3 volunteers; that correlates with a decreased expression of iNOS. [Copyright &y& Elsevier]

Usnic acid is a component of nutritional supplements promoted for weight loss that have been associated with liver-related adverse events including mild hepatic toxicity, chemical hepatitis, and liver failure requiring transplant. To determine if metabolism factors might have had a role in defining individual susceptibility to hepatotoxicity, in vitro metabolism studies were undertaken using human plasma, hepatocytes, and liver subcellular fractions. Usnic acid was metabolized to form three monohydroxylated metabolites and two regio-isomeric glucuronide conjugates of the parent drug. Oxidative metabolism was mainly by cytochrome P450 (CYP) 1A2 and glucuronidation was carried out by uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A3. In human hepatocytes, usnic acid at 20 µM was not an inducer of CYP1A2, CYP2B6, or CYP3A4 relative to positive controls omeprazole, phenobarbital, and rifampicin, respectively. Usnic acid was a relatively weak inhibitor of CYP2D6 and a potent inhibitor of CYP2C19 (the concentration eliciting 50% inhibition (IC50) = 9 nM) and CYP2C9 (IC50 = 94 nM), with less potent inhibition of CYP2C8 (IC50 = 1.9 µM) and CYP2C18 (IC50 = 6.3 µM). Pre-incubation of microsomes with usnic acid did not afford any evidence of time-dependent inhibition of CYP2C19, although evidence of slight time-dependent inhibition of CYP2C9 (KI = 2.79 µM and Kinact = 0.022 min-1) was obtained. In vitro data were used with SimCYPRto model potential drug interactions. Based on usnic acid doses in case reports of 450 mg to >1 g day-1, these in vitro data indicate that usnic acid has significant potential to interact with other medications. Individual characteristics such as CYP1A induction status, co-administration of CYP1A2 inhibitors, UGT1A1 polymorphisms, and related hyperbilirubinaemias, or co-administration of low therapeutic index CYP2C substrates could work alone or in consort with other idiosyncrasy risk factors to increase the risk of adverse events and/or hepatotoxicity. Thus, usnic acid in nutritional supplements might be involved as both victim and/or perpetrator in clinically significant drug-drug interactions. [ABSTRACT FROM AUTHOR]

The cytochrome P450 enzymes CYP2C8, CYP2C9 and CYP2J2 generate 8,9-, 11,12-, and 14,15-epoxyeicosatrienic acid (EET) from arachidonic acid, and these EETs are then hydrolyzed to dihydroxyeicosatrienoic acids (DHET) before excretion into the urine. It is unknown how genetic polymorphisms affect formation of these diuretic, vasodilatory and anti-inflammatory eicosanoids, and whether the CYP2C8 substrate rosiglitazone inhibits their formation. Methods: A panel of 14, 13 and four carriers of the CYP2C8 genotypes *1/*1, *1/*3 and *3/*3, respectively was preselected for this study. Daily morning oral doses of 8 mg rosiglitazone were administered for 15 days. Urine was collected prior to rosiglitazone, and for 24 h after the first and last administration of rosiglitazone. Urinary EETs and DHETs were analyzed by tandem mass spectrometry. Results: Carriers of the highactivity CYP2C8*3 allele had higher excretion of all three DHETs (p < 0.01 for 11,12-DHET, p < 0.05 for 14,15-DHET), whereas carriers of the low-activity CYP2C8 haplotype C (genotypes GCGA at positions rs2275622, rs7909236, rs1113129 and rs11572080) had lower DHET excretion in urine before and during rosiglitazone. Rosiglitazone intake leads to a decrease in DHET excretion by approximately 10% (p < 0.02). Urinary excretion of unhydrolyzed EETs was below the limit of quantification of 50 pg/ml in all samples. Conclusion: The data consistently indicate that genetic variation in CYP2C8 moderately modulates-EET formation as reflected in urinary DHET excretion. This might impact cardiovascular functions, and may be one mechanism explaining the influence of CYP polymorphisms on myocardial infarction and hypertension. [ABSTRACT FROM AUTHOR]

Abstract: The antimalarial drug amodiaquine is extensively metabolized to N-desethylamodiaquine (DEAQ) by cytochrome P450 2C8 (CYP2C8). DEAQ formation is an enzyme specific reaction that is used to quantify in vitro CYP2C8 activity. A rapid and sensitive method for the determination of DEAQ in human liver microsomes was developed using hydrophilic interaction liquid chromatography/tandem mass spectrometry (HILIC–MS/MS). Microsomal incubation samples were processed by protein precipitation with acetonitrile. The analytes were separated on a BETASIL Silica-100 (50mm×2.1mm, 5μm) column by isocratic elution at a flow rate of 220μl/min with a mobile phase consisting of 85% acetonitrile containing 5mM ammonium acetate and 0.1% formic acid. Detection was by positive electrospray ionization on a TSQ Quantum Discovery triple quadrupole mass spectrometer operated in the selective reaction monitoring mode. The precursor–product ion pair was m/z 328→283 for DEAQ and m/z 331→283 for DEAQ-d 3. The lower limit of quantification was 10nM for DEAQ and linearity was observed over the concentration range of 10–1500nM. Intra- and inter-day accuracy and precision were within 3.4 and 7.0%, respectively. The method was successfully applied to CYP2C8 drug metabolism studies in pooled human liver microsomes. [Copyright &y& Elsevier]

The purpose of this paper is to characterize the cytochrome P450 (CYP) enzymes involved in the metabolism of a new oral erectogenic, mirodenafil, to a major circulating active metabolite, N-dehydroxyethyl-mirodenafil, and to investigate the inhibitory potential of mirodenafil on seven CYP enzymes in human liver microsomes. CYP3A4 was identified as the major enzyme and CYP2C8 as a minor enzyme responsible for mirodenafil N-dealkylation based on correlation analysis, inhibition studies, and cDNA-expressed CYP enzyme activities. Plasma concentrations of mirodenafil and its N-dealkylated metabolite could therefore change with co-administration of known CYP3A4 inducers or inhibitors. Mirodenafil inhibited CYP3A4, CYP2C19 and CYP2D6 activities with IC50 values of 15.6, 38.2 and 77.0 µM, respectively, in human liver microsomes. However, it is very unlikely that mirodenafil will significantly alter the clearance of other compounds metabolized by CYPs 1A2, 2A6, 2C8, 2C9, 2C19, 2D6 and 3A4 because the maximum plasma concentration of mirodenafil is 0.55 µM after oral dosing of mirodenafil (100 mg) in male volunteers. [ABSTRACT FROM AUTHOR]

To analyze whether gene variants leading to impaired drug metabolism are related with acute gastrointestinal bleeding after nonsteroidal anti-inflammatory drugs (NSAID) use.Common CYP2C8 and CYP2C9 polymorphisms were studied in a cross-sectional study, involving 134 NSAID-related bleeding patients and in 177 patients receiving NSAID with no adverse effects.Among patients receiving NSAID that are CYP2C8/9 substrates the frequencies for carriers of variant alleles versus control patients were CYP2C8∗3: 0.50 vs. 0.23 [odds ratio (OR); 95% confidence interval (CI)=3.4; 1.5-7.5; P=0.002], CYP2C9∗2: 0.48 vs. 0.26 (OR; 95% CI=2.7; 1.2-5.8; P=0.013) and CYP2C9∗3: 0.24 vs. 0.20 (OR; 95% CI=1.3; 0.5-3.1; P=0.578). The frequencies for carriers of the CYP2C8∗3+CYP2C9∗2 genotype were 0.40 vs. 0.15 (OR; 95% CI=3.7; 1.6-8.9; P=0.003). These findings were not influenced by sex, age, smoking or drinking habits. Among bleeding patients receiving NSAID that are not extensively metabolized by CYP2C8/9, no differences in genotypes or allele frequencies were observed as compared with control patients.The combined presence of CYP2C8∗3 and CYP2C9∗2 (CYP2C8∗3+CYP2C9∗2 genotype), is a relevant determinant in the risk to develop gastrointestinal bleeding in patients receiving NSAID that are CYP2C8/9 substrates. [ABSTRACT FROM AUTHOR]

The cytochrome (CYP) P450 epoxygenase pathway catalyzes the epoxidation of arachidonic acids to epoxyeicosatrienoic acids, which are subsequently hydrolyzed to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase. Numerous preclinical studies have demonstrated that CYP-derived epoxyeicosatrienoic acids possess potent vasodilatory and anti-inflammatory properties in the cardiovascular system. In humans, functionally relevant polymorphisms, which may significantly modulate epoxyeicosatrienoic acid levels in vivo, have been identified in the genes encoding CYP2J2, CYP2C8, CYP2C9 and soluble epoxide hydrolase. Initial epidemiologic studies have demonstrated that genetic variation in the CYP epoxygenase pathway significantly modifies cardiovascular disease risk at the population level in humans, providing support for the hypothesis that modulation of this pathway may represent a novel approach to the prevention and treatment of cardiovascular disease. Future studies in humans validating these relationships and characterizing the underlying mechanisms will be necessary to fully understand the functional role of the CYP epoxygenase pathway in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Eupatilin, a pharmacologically active flavone derived from Artemisia plants, is extensively metabolized to eupatilin glucuronide, 4-O-desmethyleupatilin and 4-O-desmethyleupatilin glucuronide in human liver microsomes. This study characterized the human liver cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes responsible for the metabolism of eupatilin. The specific CYPs responsible for O-demethylation of eupatilin to the major metabolite, 4-O-desmethyleupatilin were identified using a combination of correlation analysis, immuno-inhibition, chemical inhibition in human liver microsomes and metabolism by human cDNA-expressed CYP enzymes. UGT enzymes involved in the eupatilin glucuronidation were identified using pooled human liver microsomes and human cDNA-expressed UGT enzymes. Eupatilin was predominantly metabolized by CYP1A2 and, to a lesser extent, CYP2C8 mediated O-demethylation of eupatilin to 4-O-desmethyleupatilin. Eupatilin glucuronidation was catalysed by UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, and UGT1A10. [ABSTRACT FROM AUTHOR]

CYP2C8 is known to metabolize various drugs including an anticancer drug paclitaxel. Although large interindividual differences in CYP2C8 enzymatic activity and several nonsynonymous variations were reported, neither haplotype structures nor their associations with pharmacokinetic parameters of paclitaxel were reported.Haplotype structures of the CYP2C8 gene were inferred by an expectation-maximization based program using 40 genetic variations detected in 437 Japanese patients, which included cancer patients. Associations of the haplotypes and paclitaxel pharmacokinetic parameters were analyzed for 199 paclitaxel-administered cancer patients.Relatively strong linkage disequilibriums were observed throughout the CYP2C8 gene. We estimated 40 haplotypes without an amino-acid change and nine haplotypes with amino acid changes. The 40 haplotypes were classified into six groups based on network analysis. The patients with heterozygous ∗IG group haplotypes harboring several intronic variations showed a 2.5-fold higher median area under concentration-time curve of C3′-p-hydroxy-paclitaxel and a 1.6-fold higher median value of C3′-p-hydroxy-paclitaxel/paclitaxel area under concentration-time curve ratio than patients bearing no ∗IG group haplotypes (P<0.001 for both comparisons by Mann-Whitney U-test). No statistically significant differences, however, were observed between patients with and without the ∗IG group (haplotypes) in clearance and area under concentration-time curve of paclitaxel, area under concentration-time curve of 6α-hydroxy-paclitaxel and 6α-, C3′-p-dihydroxy-paclitaxel, and area under concentration-time curve ratio of 6α-hydroxy-paclitaxel/paclitaxel.CYP2C8∗IG group haplotypes were associated with increased area under concentration-time curve of C3′-p-hydroxy-paclitaxel and area under concentration-time curve ratio of C3′-p-hydroxy-paclitaxel/paclitaxel. Thus, ∗IG group haplotypes might be associated with reduced CYP2C8 activity, possibly through its reduced protein levels. [ABSTRACT FROM AUTHOR]

Paclitaxel is widely used in many cancers including ovarian, breast, lung, head and neck and primary unknown. Paclitaxel is extensively metabolized by cytochrome P450s and excreted in bile. The cytochromes involved include 2C8 and 3A4. This is a review of the pharmacokinetics, pharmacodynamics, drug interactions, metabolism and pharmacogenomics of paclitaxel. [ABSTRACT FROM AUTHOR]

To identify low-penetrance genes related to sporadic essential tremor (ET) at the CYP2Clocus, located in chromosome 10 q23.33. Leukocytary DNA from 200 ET patients and a control group of 300 unrelated healthy individuals with known CYP2C19 genotypes was studied for common CYP2C8 and CYP2C9 allelic variants by using amplification-restriction analyses. Patients with ET showed the following differences compared with healthy subjects: a 1.6-fold reduction in the frequency for CYP2C8*3 ( p=0.006), a 1.35-fold reduction of CYP2C9*2 ( p=0.05) and a 1.52-fold reduction in the frequency for CYP2C9*3 ( p=0.07). The frequency for patients with ET carrying at least one defective allele was 1.33-fold reduced as compared with healthy subjects ( p=0.002). In addition, a disruption of the CYP2C8*3/CYP2C9*2 linkage disequilibrium was observed in ET patients, with a 2.1-fold reduction in the percentage for carriers of the haplotype CYP2C8*3 plus CYP2C9*2 in ET patients ( p=0.0001). These findings were independent of gender, age, age of onset, or clinical symptoms. These results suggest that alterations at the CYP2C gene locus are associated with the risk for ET. [ABSTRACT FROM AUTHOR]

Ibuprofen, a nonsteroidal anti-inflammatory agent, is metabolised in vitro by cytochrome P450 (CYP) 2C8 and 2C9. We studied the possible effect of gemfibrozil, an in vivo inhibitor of CYP2C8, on the pharmacokinetics of ibuprofen in healthy volunteers. In a randomised two-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each subject ingested 400 mg of racemic ibuprofen. Plasma concentrations of ibuprofen enantiomers and gemfibrozil were measured. Gemfibrozil raised the mean total area under the plasma concentration-time curve (AUC0–∞) of R-ibuprofen by 34% (range −10 to 67%; P < 0.001). The elimination half-lives ( t 1/2) of R- and S-ibuprofen were increased by 54 and 34% (range 11–162% and 16–85%; P < 0.001) respectively. The other pharmacokinetic variables of R- and S-ibuprofen were not changed significantly. The AUC0–∞ ratio of R-ibuprofen to S-ibuprofen was increased by gemfibrozil ( P < 0.001). Gemfibrozil moderately increases the AUC0–∞ of R-ibuprofen and prolongs its t 1/2, indicating that R-ibuprofen is partially metabolised by CYP2C8. The interconversion of R- to S-ibuprofen can explain the small effect of gemfibrozil on the t 1/2 of S-ibuprofen. The gemfibrozil-ibuprofen interaction is of limited clinical significance. [ABSTRACT FROM AUTHOR]

The cytochromes P450 epoxygenases CYP2J2 and CYP2C8 synthesize epoxyeicosatrienoic acids, which regulate endothelial function. We sought to determine if genetic variation in CYP2J2 and CYP2C8 was associated with coronary heart disease risk.We genotyped 2065 Atherosclerosis Risk in Communities study participants (1085 incident coronary heart disease cases, 980 noncases) for polymorphisms in CYP2J2 and CYP2C8. Using a case-cohort design, associations between genotype and incident coronary heart disease risk were evaluated using proportional hazards regression. The influence of cigarette smoking on these associations was also evaluated. False discovery rate q-values were estimated to minimize the impact of the multiple statistical comparisons completed. All analyses were race stratified.The CYP2J2 G-50T polymorphism variant -50T allele was associated with significantly lower risk of incident coronary heart disease in African-Americans (adjusted hazard rate ratio 0.58, 95% confidence interval 0.35-0.96, P=0.036, q=0.051); however, no significant association was observed in Caucasians. Overall, the I264M, I269F, and K399R polymorphisms in CYP2C8 were not significantly associated with risk of incident coronary heart disease. In Caucasians, the relationship between the I264M and K399R polymorphisms and incident coronary heart disease risk was significantly modified by cigarette smoking status (P for interaction=0.008, q=0.064), with the highest risk observed in smokers carrying at least one variant allele.The G-50T polymorphism in CYP2J2 may be an important risk factor for the development of coronary heart disease events in African-Americans, whereas cigarette smoking may modify the relationship between the I264M and K399R polymorphisms in CYP2C8 and coronary heart disease risk in Caucasians. Confirmation of these findings in an independent population is warranted. [ABSTRACT FROM AUTHOR]

Aims To investigate the effect of multiple dosing with montelukast, a selective leukotriene-receptor antagonist, on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Methods A two-period, randomized crossover study was conducted in 10 healthy subjects. After administration of oral doses of placebo or 10 mg montelukast daily for 6 days, 4 mg rosiglitazone was administered and plasma samples were obtained for 24 h and analyzed for rosiglitazone and N-desmethylrosiglitazone using high-performance liquid chromatography with fluorescence detection. Results During the montelukast phase, the total area under the time-concentration curve (AUC) and peak plasma concentration of rosiglitazone were 102% (90% CI 98, 107%) and 98% (90% CI 92, 103%) of the corresponding values during the placebo phase, respectively. Multiple dosing with montelukast did not affect the oral clearance of rosiglitazone significantly (90% CI 94, 105%; P = 0.50). The AUC ratio and plasma concentration ratios of N-desmethylrosiglitazone : rosiglitazone were not changed by multiple dosing with montelukast (90% CI 90, 103%; P = 0.14). Conclusions Multiple doses of montelukast do not inhibit CYP2C8-mediated rosiglitazone metabolism in vivo despite in vitro findings indicating that montelukast is a selective CYP2C8 inhibitor. [ABSTRACT FROM AUTHOR]

Abstract: We cloned a cDNA encoding a novel CYP2C enzyme, called P450 M-2C, from a marmoset liver. The deduced amino acid sequence showed high identities to those of human CYP2C8 (87%), CYP2C9 (78%) and CYP2C19 (77%). The P450 M-2C enzyme expressed in yeast cells catalyzed p-methylhydroxylation of only tolbutamide among four substrates tested, paclitaxel as a CYP2C8 substrate, diclofenac and tolbutamide as CYP2C9 substrates and S-mephenytoin as a CYP2C19 substrate. p-Methylhydroxylation of tolbutamide by marmoset liver microsomes showed monophasic kinetics, and the apparent K m value (1.2mM) for the substrate was similar to that of the recombinant P450 M-2C (1.8mM). Although all of the recombinant human CYP2C8, CYP2C9 and CYP2C19 expressed in yeast cells catalyzed tolbutamide p-methylhydroxylation, the kinetic profile of CYP2C8 was most similar to that of P450 M-2C. Tolbutamide oxidation by the marmoset liver microsomes and the recombinant P450 M-2C was inhibited most effectively by quercetin, a CYP2C8 inhibitor, followed by omeprazole, a CYP2C19 inhibitor, whereas sulfaphenazole, a CYP2C9 inhibitor, was less potent under the conditions used. These results indicate that P450 M-2C is the major tolbutamide p-methylhydroxylase in the marmoset liver. [Copyright &y& Elsevier]