Kharasch E D, Bedynek P S, Walker A, Whittington D, Hoffer C
Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St. Louis, Missouri, USA.
Clin Pharmacol Ther. 2008 Oct;84(4):506-12. doi: 10.1038/clpt.2008.102.
Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined short-term (2-day) and steady-state (2-week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P-glycoprotein (P-gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration-time curve (AUC)(0-infinity)/dose ratio (ritonavir/control) for oral ALF 25-fold. Steady-state ritonavir increased the AUC(0-Infinity)/dose ratio for IV and oral ALF 4- and 10-fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first-pass CYP3A > 96%. Chronic ritonavir inhibits hepatic CYP3A (> 70%) and first-pass CYP3A (> 90%). Acute and steady-state ritonavir increased the fexofenadine AUC(0-infinity) 2.8- and 1.4-fold, respectively, suggesting P-gp inhibition. Steady-state compared with acute ritonavir caused mild apparent induction of P-gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir.
利托那韦可降低美沙酮的血浆浓度，这一效应归因于细胞色素P450 3A（CYP3A）的诱导作用，但其实际机制尚不清楚。我们测定了利托那韦对肠道和肝脏CYP3A4/5（通过静脉注射（IV）和口服阿芬太尼（ALF）以及瞳孔缩小进行检测）和P-糖蛋白（P-gp）（非索非那定）的短期（2天）和稳态（2周）效应，以及对健康志愿者中美沙酮药代动力学和药效学的影响。急性给予利托那韦使口服ALF的浓度-时间曲线下面积（AUC）（0至无穷大）/剂量比（利托那韦/对照）增加了25倍。稳态利托那韦使静脉注射和口服ALF的AUC（0至无穷大）/剂量比分别增加了4倍和10倍；降低了肝脏清除率（从0.26降至0.07）和肠道清除率（从0.51降至0）；并提高了生物利用度（从37%提高到95%）。急性利托那韦抑制首过CYP3A的程度>96%。慢性利托那韦抑制肝脏CYP3A（>70%）和首过CYP3A（>90%）。急性和稳态利托那韦分别使非索非那定的AUC（0至无穷大）增加了2.8倍和1.4倍，提示对P-gp有抑制作用。与急性利托那韦相比，稳态利托那韦导致P-gp和肝脏CYP3A有轻度的表观诱导，但净抑制作用仍然占主导。利托那韦抑制肠道和肝脏的CYP3A以及药物转运。ALF引起的瞳孔缩小可用于非侵入性地测定利托那韦对CYP3A的抑制作用。
