Exploring the Drug-Drug Interaction Between Gemfibrozil and Repaglinide in Rats
Full Title
Exploring the Drug-Drug Interaction Between Gemfibrozil and Repaglinide in Rats: Metabolism and Transport
Abstract
A clinically-relevant drug-drug interaction (DDI) between the dyslipidemia drug gemfibrozil and the antidiabetic repaglinide is well-documented throughout the literature. In humans, repaglinide is predominantly cleared by hepatic metabolism involving cytochrome P450 (CYP) 3A4 and 2C8 and UGT1A1 and 1A3. Gemfibrozil and its glucuronide metabolite inhibit CYP2C8 (irreversibly) and UGT1A1, which has been proposed as a key cause of the clinical interaction. Additionally, gemfibrozil and gemfibrozil glucuronide are established inhibitors of the hepatic uptake transporter OATP1B1, proposed as a confounding factor. A mechanistic assessment of the gemfibrozil/repaglinide DDI was undertaken in male Sprague-Dawley rats. Subjects (n = 3/group) received 200 mg/kg/day gemfibrozil or vehicle control by oral gavage for 2 days. On day 3, rats were fasted for 12 h and dosed once orally with 1 mg/kg repaglinide coadministered with gemfibrozil or vehicle. Blood, bile and urine were collected for 12 h following repaglinide administration. Livers were extracted for microsome preparation. In-life work was performed by Xenometrics LLC (Stilwell, KS). Rat plasma time-points, Hamilton-pooled plasma, and 0-12 h urine and bile pools were analyzed by LC-MS/MS for pharmacokinetics (PK) and metabolite profiling. P450 and UGT enzyme activities in liver microsomes were analyzed by LC-MS/MS. Gemfibrozil treatment greatly reduced repaglinide clearance in rats. Gemfibrozil-treated rats exhibited a 4-fold higher repaglinide Cmax and a 3.5-fold greater AUC0-12 than control rats, but the tmax (1.2 and 1.7 h) and t1/2 (2.6 h) values were similar. The Vd,obs and plasma CLobs were approximately two-thirds lower in gemfibrozil-treated rats than control rats.