Renal organic anion transporter-mediated drug-drug interaction between gemcabene and quinapril.
In humans and rats, a synergistic blood pressure reduction was observed when the fibrate gemcabene (CI-1027) was coadministered 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 area under the curve from 0 to 24 h of the active metabolite quinaprilat when coadministered 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 human embryonic kidney 293 cells transfected with human or rat organic anion transporter 3 (hOAT3, rOat3) revealed that quinaprilat is a substrate in both species, with a K(m) value of 13.4 microM for hOAT3. Subsequent studies discovered that gemcabene inhibited quinaprilat uptake by hOAT3 and rOat3 at IC(50) values of 35 and 48 microM, respectively. Moreover, gemcabene acylglucuronide, the major metabolite of gemcabene glucuronidation, also inhibited hOAT3- and rOat3-mediated uptake of quinaprilat at IC(50) values of 197 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.
Yuan
Haodan
H
Department of Pharmacokinetics Pharmacokinetic, Dynamics, and Metabolism, Pfizer, Inc. St. Louis Laboratory, 700 Chesterfield Pkwy. West, Chesterfield, MO 63017, USA. haodan.yuan@pfizer.com
Feng
Bo
B
Yu
Ying
Y
Chupka
Jonathan
J
Zheng
Jenny Y
JY
Heath
Timothy G
TG
Bond
Brian R
BR
D000818:Animals; D002208:Caproates / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D002460:Cell Line; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D000077583:Quinapril; D051381:Rats; D011918:Rats, Inbred SHR; D044005:Tetrahydroisoquinolines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics
D002208:Caproates; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D044005:Tetrahydroisoquinolines; C114338:organic anion transport protein 3; C111024:gemcabene; D000077583:Quinapril