Trandolaprilat, an angiotensin-converting enzyme inhibitor, is not excreted in bile via an ATP-dependent active transporter (cMOAT)

Trandolapril is the prodrug of an angiotensin-converting enzyme (ACE) inhib itor. It has been proposed that its active metabolite, trandolaprilat, is m ainly excreted in bile, but this has not been clearly demonstrated. Recentl y it has been reported that temocaprilat, an active metabolite of the ACE i nhibitor temocapril, is effectively excreted in bile via an ATP-dependent a ctive transporter (canalicular multispecific organic anion transporter: cMO AT), To investigate whether trandolaprilat has the pharmacological ability to affect the cMOAT system in a manner similar to temocaprilat. The lipophi licity of trandolaprilat and temocaprilat was measured to determine the eta -octanol-water partition coefficients. The dose-dependent inhibition of th e uptake of [H-3]-estradiol-17 beta -D-glucuronide and [H-3]-2,4-dinitrophe nyl-S-glutathione, which are good substrates for cMOAT, in canalicular memb rane vesicles (CMVs) prepared from Sprague-Dawley rats was determined in th e presence of trandolaprilat and temocaprilat, The partition coefficient of trandolaprilat (log Po/w - 1.1) was about 30 times higher than that of tem ocaprilat(log Po/w - 2.5). The uptake of [H-3]estradiol-17 beta -D-glucuron ide and [H-3]-2,4-dinitrophenyl-S-glutathione was dose-dependently inhibite d by the presence of temocaprilat, but trandolaprilat had no effect on the transport of [H-3]-estradiol-17 beta -D-glucuronide or [H-3]-2,4-dinitrophe nyl-S-glutathione into CMVs even at concentrations as high as 200 muM, R co uld be concluded that trandolaprilat has a higher lipophilicity than temoca prilat, But the hepatobiliary excretion system via cMOAT may not contribute to the excretion of trandolaprilat in bile.