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Phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) are new antimitotic prodrugs bioactivated by the enzyme CYP1A1 into phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB-SOs) that are potently (nM) and selectively inhibiting the growth of CYP1A1-expressing breast cancer cells. The screening program identified three PAIB-SOs designated as CEU-835, CEU-934, and CEU-938 for further pharmacokinetic studies. A novel method for their quantification in CD-1® IGS female mouse plasma using a Waters UHPLC ACQUITY Arc system was developed and validated. Their analytical measurements ranged from 7.3 to 1484 ng/mL. They exhibited linearity between 7.3 and 1484 ng/mL. They also showed good resolutions (2.21–4.99) and good theoretical plate numbers (14707–70580). Moreover, they were robust at wavelengths between 273 and 310 nm and sensitive from 2 to 62 AU/ng mL−1. This new method is indispensable to assess PAIB-SOs half-life in mouse plasma and for the quantification of PAIB-SOs in other biological matrices. [ABSTRACT FROM AUTHOR]

Aims: Some population pharmacokinetic models have been developed using height to explain some of the interindividual variability in tobramycin pharmacokinetics in cystic fibrosis patients. However, their predictive performance when extrapolated to other clinical centres is unclear. Therefore, the aim of this study was to externally evaluate the predictability of tobramycin population pharmacokinetic models with an independent dataset and perform simulations using previously recommended height‐based dosing regimens. Methods: A literature search was conducted through the PubMed database to identify relevant population pharmacokinetic models. Tobramycin plasma concentration data from April 2014 to November 2019 were retrospectively collected from the Institut universitaire de cardiologie et de pneumologie de Québec, Canada. External evaluations were performed using NONMEM® v7.5 and RStudio® v1.3.1073. Monte Carlo simulations were performed to evaluate the probability of target attainment of Cmax/MIC ratios for several dosing regimens. Results: The validation dataset included 27 patients and 143 concentration samples. Three models were evaluated. Only the ones by Crass et al. and Alghanem et al. performed satisfactorily in terms of prediction‐based diagnostics with MDPE values of −3.4% and 29.3% and MDAPE values of 19.0 and 29.5%, respectively. In simulation‐based evaluations, both pcVPC and NPDE showed no evidence of model misspecification. Our simulations suggest that patients treated with a once‐daily dose of 3.4 mg/cm should produce peak and trough levels consistent with current guidelines. Conclusion: Our results show that the models by Crass et al. and Alghanem et al. are appropriate for simulation‐based applications to aid individualized dosing in our population and that height‐based dosing regimens could be considered in cystic fibrosis patients. [ABSTRACT FROM AUTHOR]

Cardiac arrhythmias and ECG abnormalities including bradycardia, prolongation of the QT interval, and atrioventricular ( AV) conduction blocks have been extensively observed with fingolimod, the first marketed oral drug for treating the relapsing-remitting form of multiple sclerosis. This study was aiming to further elucidate the effects of fingolimod on cardiac electrophysiology at three different levels: (i) in vitro, (ii) ex vivo , and (iii) in vivo. (i) Patch-clamp experiments in whole cell configuration were performed on Cav1.2-transfected tsA201 cells exposed to fingolimod-phosphate 100 or 500 nmol/L ( n = 27 cells, total) to measure drug effect on L-type calcium current ( ICaL). (ii) Langendorff perfusion experiments were undertaken on male Hartley guinea-pigs isolated hearts ( n = 4) exposed to fingolimod 10 and 100 nmol/L to evaluate drug-induced effects on monophasic action potential duration measured at 90% repolarization ( MAPD90). (iii) Implanted cardiac telemeters were used to record ECGs in guinea-pigs ( n = 7) treated with a single dose of fingolimod 0.0625 mg/kg suspension, administered as an oral gavage. (i) In vitro cellular experiments showed that fingolimod-phosphate causes a concentration-dependent reduction in ICaL. (ii) Ex vivo Langendorff experiments revealed that fingolimod had no significant effect on MAPD90. (iii) Fingolimod caused significant prolongations of the RR, PR, QT, and QTcF intervals in vivo. Reversible AV blocks were also observed in 7/7 animals. Fingolimod possesses ICaL-blocking properties, further contributing to its AV conduction-slowing effects. These properties are also consistent with its mitigated effect on the QT interval in humans, despite previously shown HERG-blocking effect. [ABSTRACT FROM AUTHOR]

CYP3A4, the most abundant cytochrome P450 enzyme in the human liver and small intestine, is responsible for the metabolism of about 50% of all marketed drugs. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Evidences suggest that drug disposition is altered in type 1 (T1D) and type 2 diabetes (T2D). The objective was to evaluate the effect of T1D and T2D on hepatic and intestinal CYP3a drug-metabolizing activity/expression in mice. Hepatic and intestinal microsomes were prepared from streptozotocin-induced T1D, db/db T2D and control mice. Domperidone was selected as a probe substrate for CYP3a and formation of five of its metabolites was evaluated using high performance liquid chromatography. Hepatic CYP3a protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction respectively. Hepatic microsomal CYP3a activity was significantly increased in both T1D and T2D groups versus control group. Intestinal CYP3a activity was also significantly increased in both T1D and T2D groups. Moreover, significant increases of both hepatic CYP3a mRNAs and protein expression were observed in both T1D and T2D groups versus control group. Additional experiments with testosterone further validated the increased activity of CYP3a under the effect of both T1D and T2D. Although differences exist in the pathophysiological insults associated with T1D and T2D, our results suggest that these two distinct diseases may have the same modulating effect on the regulation of CYP3a, ultimately leading to variability in drug response, ranging from lack of effect to life-threatening toxicity. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine if sex influences the pharmacokinetics and hemodynamics of the CYP2D6 substrate metoprolol and its interaction with diphenhydramine (CYP2D6 inhibitor) in healthy young participants with high (extensive metabolizer [EM]) or low (poor metabolizer [PM]) CYP2D6 activities. A prespecified comparative analysis of data from 2 sequential clinical trials that included 16 EM and 4 PM women and 10 EM and 6 PM men was performed. The participants in the 2 trials were administered a single oral dose of 100 mg metoprolol in the presence of steady-state diphenhydramine or placebo. Serial plasma and urine samples were obtained for 48 hours, and hemodynamic data was obtained for 12 hours after metoprolol. In the placebo arm, EM and PM women had 62% and 59% higher S-metoprolol AUC(0-infinity) and 26% and 71% lower CL/F, respectively, compared to men with the same phenotype (all Ps < .05 women compared to men). These differences dissipated on body weight (WT) correction. Women (especially PMs) experienced greater negative chronotropic effects of metoprolol than men (P < .0001 women compared to men). Diphenhydramine coadministration increased S-metoprolol AUC by 84% in EM women and 45% in EM men (P < .009 women compared to men). In the diphenhydramine arm, sex differences in pharmacokinetics persisted even after WT correction, resulting in greater negative chronotropic effects in women (all Ps < .05 women compared to men). Metoprolol dose should be adjusted for body weight, particularly in women. Coadministration of a CYP2D6 inhibitor such as diphenhydramine, by a patient at similar doses in the 2 sexes, could result in a greater inhibition of clearance of CYP2D6 substrates with a resulting higher risk of pronounced pharmacological and adverse effects in women compared to men.

Background: Brugada syndrome (BS) is an electrical cardiac disorder with a right bundle branch block and ST segment elevation in leads V1 to V3 on surface electrocardiograms (ECGs), and is a syndrome that may lead to sudden cardiac death., Purpose: The aim of the present study was to screen for mutations in the SCN5A gene in a family with BS, and to characterize the consequences of the mutation on channel function., Results: A heterozygous nonsense SCN5A mutation (W822X) was identified in the index patient. The mutation was confirmed in the patient's asymptomatic 16-year-old brother and 48-year-old father. The mutation was absent in the index patient's sister and mother. The ECG of the index patient showed a BS type 2 ECG phenotype, which converted into a type 1 ECG phenotype in the presence of flecainide. The ECG of the patient's brother was not typical for BS, but ajmaline treatment unmasked a type 1 ECG phenotype. The ECG of the asymptomatic father was normal at baseline and in the presence of ajmaline. No Na+ currents could be measured in tsA201 cells transfected with W822X mutant channels. Heterozygote expression showed a nearly 50% reduction in Na+ current amplitude with no significant alterations of biophysical properties, indicating a loss of functional Na+ channels, obviously without any dominant-negative activity on wild type channels., Conclusions: The haploinsufficiency of the Nav1.5 protein is the plausible explanation for the clinical BS phenotype in this family. Because the heterozygous W822X mutation theoretically leads to channel expression at one-half of the normal level, the authors suggest that a modifier gene may influence or rescue the phenotype in the asymptomatic family members.