Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
Drug Metab Dispos. 2011 Jun;39(6):1070-8. doi: 10.1124/dmd.110.037523. Epub 2011 Mar 15.
Conflicting drug-drug interaction (DDI) studies with the HIV protease inhibitors (PIs) suggest net induction or inhibition of intestinal or hepatic CYP3A. As part of a larger DDI study in healthy volunteers, we determined the effect of extended administration of two PIs, ritonavir (RTV) or nelfinavir (NFV), or the induction-positive control rifampin on intestinal and hepatic CYP3A activity as measured by midazolam (MDZ) disposition after a 14-day treatment with the PI in either staggered (MDZ ∼12 h after PI) or simultaneous (MDZ and PI coadministered) manner. Oral and intravenous MDZ areas under the plasma concentration-time curves were significantly increased by RTV or NFV and were decreased by rifampin. Irrespective of method of administration, RTV decreased net intestinal and hepatic CYP3A activity, whereas NFV decreased hepatic but not intestinal CYP3A activity. The magnitude of these DDIs was more accurately predicted using PI CYP3A inactivation parameters generated in sandwich-cultured human hepatocytes rather than human liver microsomes.
与 HIV 蛋白酶抑制剂（PI）相关的药物相互作用（DDI）研究结果不一，提示肠道或肝脏 CYP3A 出现净诱导或净抑制。在一项健康志愿者的更大规模 DDI 研究中，我们测定了在 staggered （MDZ 约在 PI 后 12 小时）或 simultaneous （MDZ 和 PI 同时给予）方式下，给予利托那韦（RTV）或奈非那韦（NFV）（或阳性诱导对照 rifampin）两种 PI 药物延长给药后，米达唑仑（MDZ）处置对肠道和肝脏 CYP3A 活性的影响，PI 治疗 14 天后测定 MDZ 分布。RTV 或 NFV 使 MDZ 的口服和静脉 AUC 显著增加，而 rifampin 使 AUC 减少。无论给药方式如何，RTV 均降低净肠道和肝脏 CYP3A 活性，而 NFV 仅降低肝脏 CYP3A 活性而不影响肠道 CYP3A 活性。使用三明治培养人肝细胞而非人肝微粒体生成的 PI 对 CYP3A 抑制参数更准确地预测了这些 DDI。
