| Title | Renal Organic Anion Transporter Mediated Drug-Drug Interaction between Gemcabene and Quinapril. | | Author(s) | Yuan H, Feng B, Yu Y, Chupka J, Zheng JY, Heath TG, Bond BR | | Institution | Pfizer Inc. | | Source | J Pharmacol Exp Ther 2009 Apr 6. | | Abstract | In humans and rats, a synergistic blood pressure reduction was observed when the fibrate gemcabene (CI-1027) was co-administrated with the angiotensin-converting enzyme inhibitor, quinapril. In a quinapril (3 mg/kg) pharmacokinetic rat study, there was a 40% decrease in urinary excretion and a 53% increase in plasma AUC(0-24hr) of the active metabolite, quinaprilat, when co-administered with gemcabene (30 mg/kg). This observation revealed a possible transporter mediated drug-drug interaction (DDI) between gemcabene and quinapril. This led to a series of studies investigating the underlying clearance mechanisms associated with these compounds intended to elucidate renal transporter interactions between quinapril and gemcabene. In vitro transporter studies using HEK293 cells transfected with human or rat organic anion transporter 3 (hOAT3, rOat3) revealed that quinaprilat is a substrate in both species, with a Km value of 13.4 microM for hOAT3. Subsequent studies discovered that gemcabene inhibited quinaprilat uptake by hOAT3 and rOat3 at IC50s of 35 microM and 48 microM, respectively. Moreover, the major metabolite of gemcabene glucuronidation, gemcabene acylglucuronide, also inhibited hOAT3 and rOat3 mediated uptake of quinaprilat at IC50s of 197 microM and 133 microM, respectively. High plasma concentrations of gemcabene (>100 microM) achieved in humans and rats upon oral dosing corroborate with gemcabene inhibition of renal OAT3-mediated secretion of quinaprilat in vitro. This investigation established that a DDI between gemcabene and quinapril involving inhibition of renal transporters and subsequent elevation in plasma concentrations of quinaprilat is responsible for the apparent synergistic blood pressure reduction observed with these compounds. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19349522 |
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