Influence of CYP3A5 Genotype on the Pharmacokinetics and Pharmacodynamics of the Cytochrome P4503A Probes Alfentanil and Midazolam

Abstract

The hepatic and first-pass cytochrome P4503A (CYP3A) probe alfentanil (ALF) is also metabolized in vitro by CYP3A5. Human hepatic microsomal ALF metabolism is higher in livers with at least one CYP3A5*1 allele and higher CYP3A5 protein content, compared with CYP3A5*3 homozygotes with little CYP3A5. The influence of CYP3A5 genotype on ALF pharmacokinetics and pharmacodynamics was studied, and compared to midazolam (MDZ), another CYP3A probe. Healthy volunteers (58 men, 41 women) were genotyped for CYP3A5 *1, *3, *6, and *7 alleles. They received intravenous MDZ then ALF, and oral MDZ and ALF the next day. Plasma MDZ and ALF concentrations were determined by mass spectrometry. Dark-adapted pupil diameters were determined coincident with blood sampling. In CYP3A5(*)3/(*)3 (n=62), (*)1/(*)3 (n=28), and (*)1/(*)1 (n=8) genotypes, systemic clearances of ALF were 4.6+/-1.8, 4.8+/-1.7, and 3.9+/-1.7 ml/kg/min and those of MDZ were 7.8+/-2.3, 7.7+/-2.3, and 6.0+/-1.4 ml/kg/min, respectively (not significant), and apparent oral clearances were 11.8+/-7.2, 13.3+/-6.1, and 12.6+/-8.2 ml/kg/min for ALF and 35.2+/-19.0, 36.4+/-15.7, and 29.4+/-9.3 ml/kg/min for MDZ (not significant). Clearances were not different between African Americans (n=25) and Whites (n=68), or between CYP3A5 genotypes within African Americans. ALF pharmacodynamics was not different between CYP3A5 genotypes. There was consistent concordance between ALF and MDZ, in clearances and extraction ratios. Thus, in a relatively large cohort of healthy subjects with constitutive CYP3A activity, CYP3A5 genotype had no effect on the systemic or apparent oral clearances, or pharmacodynamics, of the CYP3A probes ALF and MDZ, despite affecting their hepatic microsomal metabolism.

In Vitro Kinetic Characterization of Axitinib Metabolism

“…These results are consistent with the in vitro findings that CYP2C19 and UGT1A1 play a minor role in the overall clearance from the body. While CYP3A enzymes, especially CYP3A4, are clearly important in the metabolism of axitinib, the lack of correlation of pharmacokinetic variability with specific genotypes of CYP3A is consistent with the lack of phenotype-genotype correlations reported for other CYP3A substrates such as diltiazem, midazolam, nifedipine, and oxycodone (Floyd et al, 2003;Kharasch et al, 2007;Tomalik-Scharte et al, 2008;Naito et al, 2011;Haas et al, 2013;Zheng et al, 2013), where the pharmacokinetic variability can be attributed to the inherent range of CYP3A4 expression in the population, regardless of polymorphism. Additionally, investigations of pharmacokinetic variability seen in the clinic for axitinib, in lieu of the putative in vitro data supporting the prominent CYP3A4 role in axitinib clearance, include CYP3A4*22 polymorphism assessment from the collected genotyping samples.…”

Relative Contributions of Cytochrome CYP3A4 Versus CYP3A5 for CYP3A-Cleared Drugs Assessed In Vitro Using a CYP3A4-Selective Inactivator (CYP3cide)

“…These trials include many studies investigating the effect of CYP3A genotype on exposure, where the results have been mixed (Wandel et al, 2000;Shih and Huang, 2002;Floyd et al, 2003;Wong et al, 2004;Yu et al, 2004;He et al, 2005;Lepper et al, 2005;Kharasch et al, 2007;Tomalik-Scharte et al, 2008;de Jonge et al, 2013;Elens et al, 2013). However, in a recent extensive clinical study conducted by Elens and colleagues (2013), 108 CYP3A4 and CYP3A5 genotyped cancer patients were giving an i.v.…”

No role for the CYP3A5*3 polymorphism in intestinal and hepatic metabolism of midazolam

“…Recently, in Clinical Pharmacology and Therapeutics, Kharasch et al [1] published a study on the role of CYP3A5 polymorphisms in the pharmacokinetics and pharmacodynamics of the CYP3A probe drugs alfentanil and midazolam, both CYP3A4 and CYP3A5 substrates.…”