Zheng H X, Huang Y, Frassetto L A, Benet L Z
Department of Biopharmaceutical Sciences, University of California, San Francisco, San Francisco, California, USA.
Clin Pharmacol Ther. 2009 Jan;85(1):78-85. doi: 10.1038/clpt.2008.186. Epub 2008 Oct 8.
The effects of single doses of intravenous (IV) ciprofloxacin and rifampin and of multiple doses of rifampin on glyburide exposure and blood glucose levels were investigated in nine healthy volunteers. A single IV dose of rifampin significantly increased the area under the concentration-time curve (AUC) of glyburide and its metabolite. Blood glucose levels were significantly lower than those observed after dosing with glyburide alone. Multiple doses of rifampin induced an increase in liver enzyme levels, leading to a marked decrease in glyburide exposure and blood glucose levels. When IV rifampin was administered after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect; however, the relative changes in AUC for glyburide and its hydroxyl metabolite were similar to those seen under noninduced conditions. The studies reported here demonstrate how measurements of the levels of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and in characterizing enzymatic vs. transporter mechanisms.
在9名健康志愿者中研究了单剂量静脉注射环丙沙星和利福平以及多剂量利福平对格列本脲暴露量和血糖水平的影响。单剂量静脉注射利福平显著增加了格列本脲及其代谢物的浓度-时间曲线下面积（AUC）。血糖水平显著低于单独服用格列本脲后观察到的水平。多剂量利福平导致肝酶水平升高，导致格列本脲暴露量和血糖水平显著降低。在多剂量利福平后静脉注射利福平时，肝摄取转运体的抑制掩盖了诱导作用；然而，格列本脲及其羟基代谢物的AUC相对变化与非诱导条件下观察到的相似。此处报道的研究表明，母体药物及其主要代谢物水平的测量如何有助于揭示同时存在的药物-药物诱导和抑制作用，以及如何表征酶促与转运体机制。
