Kharasch E D, Walker A, Isoherranen N, Hoffer C, Sheffels P, Thummel K, Whittington D, Ensign D
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, Missouri, USA.
Clin Pharmacol Ther. 2007 Oct;82(4):410-26. doi: 10.1038/sj.clpt.6100237. Epub 2007 Jun 6.
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 CYP3A51 allele and higher CYP3A5 protein content, compared with CYP3A53 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.
肝脏及首过效应细胞色素P4503A（CYP3A）探针药物阿芬太尼（ALF）在体外也可被CYP3A5代谢。与几乎没有CYP3A5的CYP3A53纯合子相比，具有至少一个CYP3A51等位基因且CYP3A5蛋白含量较高的肝脏中，人肝微粒体对ALF的代谢能力更强。本研究探讨了CYP3A5基因型对ALF药代动力学和药效学的影响，并与另一种CYP3A探针咪达唑仑（MDZ）进行比较。对健康志愿者（58名男性，41名女性）的CYP3A5 1、3、6和7等位基因进行基因分型。他们先静脉注射MDZ，然后注射ALF，第二天口服MDZ和ALF。采用质谱法测定血浆MDZ和ALF浓度。在采血的同时测定暗适应瞳孔直径。在CYP3A5（）3/（）3（n = 62）、（）1/（）3（n = 28）和（）1/（）1（n = 8）基因型中，ALF的全身清除率分别为4.6±1.8、4.8±1.7和3.9±1.7 ml/kg/min，MDZ的全身清除率分别为7.8±2.3、7.7±2.3和6.0±1.4 ml/kg/min（差异无统计学意义），ALF的表观口服清除率分别为11.8±7.2、13.3±6.1和12.6±8.2 ml/kg/min，MDZ的表观口服清除率分别为35.2±19.0、36.4±15.7和29.4±9.3 ml/kg/min（差异无统计学意义）。非裔美国人（n = 25）和白人（n = 68）之间，以及非裔美国人内部不同CYP3A5基因型之间的清除率均无差异。不同CYP3A5基因型之间ALF的药效学无差异。ALF和MDZ在清除率和提取率方面具有一致的相关性。因此，在一组具有组成性CYP3A活性的相对较大的健康受试者队列中，尽管CYP3A5基因型影响CYP3A探针ALF和MDZ的肝微粒体代谢，但对其全身或表观口服清除率以及药效学并无影响。
