TY - JOUR T1 - Transport of Temocaprilat into Rat Hepatocytes: Role of Organic Anion Transporting Polypeptide <span class="xref-sep">,</span> JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 37 LP - 42 VL - 287 IS - 1 AU - Hitoshi Ishizuka AU - Kumiko Konno AU - Hideo Naganuma AU - Kenji Nishimura AU - Hirokazu Kouzuki AU - Hiroshi Suzuki AU - Bruno Stieger AU - Peter J. Meier AU - Yuichi Sugiyama Y1 - 1998/10/01 UR - http://jpet.aspetjournals.org/content/287/1/37.abstract N2 - The mechanism for hepatic uptake of temocaprilat, an angiotensin-converting enzyme inhibitor that is predominantly excreted into bile was studied using isolated rat hepatocytes and COS-7 cells expressing the organic anion transporting polypeptide (oatp1). The uptake of temocaprilat into isolated rat hepatocytes exhibited saturation with a Km of 20.9 μM and a Vmax of 0.21 nmol/min/mg protein. This uptake was temperature sensitive and was significantly reduced by metabolic inhibitors, a sulfhydryl-modifying reagent and an anion-exchange inhibitor, although the replacement of Na+ with Li+ in the medium did not affect the uptake. [3H]Temocaprilat uptake was inhibited by estradiol-17β-d-glucuronide and dibromosulphophthalein, typical substrates for the Na+-independent organic anion transporter, in a concentration-dependent manner, whereas excess estradiol-17β-d-glucuronide did not completely inhibit the uptake. Temocaprilat uptake into COS-7 cells transfected with oatp1 cDNA revealed a concentration-dependency with aKm of 46.7 μM, a value comparable with that obtained in isolated hepatocytes. The contribution of oatp1 to carrier-mediated hepatic uptake of temocaprilat was less than 50% by correcting the uptake clearance with that of estradiol-17β-d-glucuronide. A good linear correlation was observed for the inhibitory effect of angiotensin-converting enzyme inhibitors (benazeprilat, cilazaprilat, delaprilat and enalaprilat) between isolated hepatocytes and oatp1-expressing cells. These data suggest that oatp1, along with another transporter(s), mediates the uptake of angiotensin-converting enzyme inhibitors into rat hepatocytes. The American Society for Pharmacology and Experimental Therapeutics ER -