Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide.

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Ishizuka H, Konno K, Naganuma H, Nishimura K, Kouzuki H, Suzuki H, Stieger B, Meier PJ, Sugiyama Y

Transport of temocaprilat into rat hepatocytes: role of organic anion transporting polypeptide.

J Pharmacol Exp Ther. 1998 Oct;287(1):37-42.

PubMed ID

9765319 [ View in PubMed

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Abstract

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 microM 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-17beta-D-glucuronide and dibromosulphophthalein, typical substrates for the Na+-independent organic anion transporter, in a concentration-dependent manner, whereas excess estradiol-17beta-D-glucuronide did not completely inhibit the uptake. Temocaprilat uptake into COS-7 cells transfected with oatp1 cDNA revealed a concentration-dependency with a Km of 46.7 microM, 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-17beta-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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Temocapril	Solute carrier organic anion transporter family member 1A2	Protein	Humans	Unknown	Not Available	Details