Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands.
J Pharm Sci. 2011 Jun;100(6):2508-15. doi: 10.1002/jps.22457. Epub 2010 Dec 29.
Lopinavir, a human immunodeficiency virus protease inhibitor, has a very low oral bioavailability, which can be enhanced with a low dose of the CYPA4 inhibitor ritonavir. Our aim was to separately quantify the role of intestinal and hepatic cytochrome P450 3A (CYP3A4) expression on lopinavir disposition in a novel mouse model. Lopinavir and ritonavir were administered to mice selectively expressing human CYP3A4 in the intestine and/or liver. Using nonlinear mixed-effects modeling, we could separately quantify the effects of intestinal CYP3A4 expression, hepatic CYP3A4 expression, and the presence of ritonavir on both the absorption and elimination of lopinavir, which was previously not possible using noncompartmental methods. Intestinal, but not hepatic, CYP3A4-related first-pass metabolism was the major barrier for systemic entry of lopinavir. Relative oral bioavailability of lopinavir in mice expressing both hepatic and intestinal CYP3A4 was only 1.3% when compared with mice that were CYP3A deficient. In presence of ritonavir, relative bioavailability increased to 9.5% due to inhibiton of intestinal, but not due to inhibition of hepatic first-pass metabolism. Hepatic CYP3A4 related systemic clearance was inversely related to ritonavir exposure and not only hepatic but also intestinal CYP3A4 expression contributed to systemic clearance of lopinavir.
洛匹那韦是一种人类免疫缺陷病毒蛋白酶抑制剂，其口服生物利用度非常低，低剂量的细胞色素 P450 3A（CYP3A4）抑制剂利托那韦可提高其生物利用度。我们的目的是在一种新型小鼠模型中分别定量研究肠道和肝脏细胞色素 P450 3A（CYP3A4）表达对洛匹那韦处置的作用。将洛匹那韦和利托那韦分别给予在肠道和/或肝脏中选择性表达人 CYP3A4 的小鼠。通过非线性混合效应模型，我们可以分别定量评估肠道 CYP3A4 表达、肝脏 CYP3A4 表达以及利托那韦对洛匹那韦吸收和消除的影响，这在以前使用非房室方法是不可能的。肠道而非肝脏 CYP3A4 相关的首过代谢是洛匹那韦全身进入的主要障碍。与 CYP3A 缺乏的小鼠相比，在同时表达肝和肠 CYP3A4 的小鼠中，洛匹那韦的相对口服生物利用度仅为 1.3%。在利托那韦存在的情况下，由于抑制了肠道而不是肝脏的首过代谢，相对生物利用度增加到 9.5%。肝 CYP3A4 相关的全身清除率与利托那韦暴露呈反比，不仅肝而且肠 CYP3A4 表达都有助于洛匹那韦的全身清除。
