title: 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.
authors.affiliation: Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, Missouri, USA. kharasch@wustl.edu
authors.forename: E D
authors.initials: ED
authors.lastname: Kharasch
authors.forename: A
authors.initials: A
authors.lastname: Walker
authors.forename: N
authors.initials: N
authors.lastname: Isoherranen
authors.forename: C
authors.initials: C
authors.lastname: Hoffer
authors.forename: P
authors.initials: P
authors.lastname: Sheffels
authors.forename: K
authors.initials: K
authors.lastname: Thummel
authors.forename: D
authors.initials: D
authors.lastname: Whittington
authors.forename: D
authors.initials: D
authors.lastname: Ensign
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001741:Black or African American / Q000235:genetics; D015760:Alfentanil / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D015877:Miosis / Q000139:chemically induced; D010641:Phenotype; D011110:Polymorphism, Genetic; D011680:Pupil / Q000187:drug effects; D012016:Reference Values; D013379:Substrate Specificity; D044465:White People / Q000235:genetics
chemical_list: D015415:Biomarkers; D015760:Alfentanil; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam