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.

Efavirenz diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but actual mechanisms are unknown. This investigation determined the effects of two weeks of efavirenz (600 mg daily) on hepatic and intestinal CYP3A4/5 (probed with intravenous and oral alfentanil), hepatic CYP2B6 (oral efavirenz hydroxylation) and intestinal transporter (oral fexofenadine) activities, and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. It also assessed efavirenz effects on CYP expression and activity in human hepatocytes. Efavirenz significantly induced systemic and oral alfentanil clearance 2- to 5-fold, increased alfentanil hepatic and intestinal extraction ratios, and significantly induced apparent 8-hydroxyefavirenz formation clearance. Efavirenz also moderately decreased fexofenadine plasma concentrations, suggesting decreased intestinal uptake and/or increased P-glycoprotein-mediated efflux. Efavirenz induced CYP2B6 and CYP3A4 expression, activity, and methadone metabolism in human hepatocytes. Efavirenz coinduces hepatic CYP2B6 and CYP3A4/5 activities, coinduces hepatic and intestinal CYP3A4/5, and coinduces gastrointestinal CYP3A and xenobiotic efflux transporters.

Methoxyflurane nephrotoxicity seems to result from O-demethylation, which forms both fluoride and DCAA. Because their co-formation is unique to methoxyflurane compared with other volatile anesthetics and they are more toxic than fluoride alone, this suggests a new hypothesis of methoxyflurane nephrotoxicity. This may explain why increased fluoride formation from methoxyflurane, but not other anesthetics, is associated with toxicity. These results may have implications for the interpretation of clinical anesthetic defluorination, use of volatile anesthetics, and the laboratory methods used to evaluate potential anesthetic toxicity.