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

Ishizuka, H. and Konno, K. and Naganuma, H. and Nishimura, K. and Kouzuki, H. and Suzuki, H. and Stieger, B. and Meier, P. J. and Sugiyama, Y.. (1998) Transport of temocaprilat into rat hepatocytes : role of organic anion transporting polypeptide. The Journal of Pharmacology and Experimental Therapeutics, Vol. 287, H. 1. pp. 37-42.

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Official URL: http://edoc.unibas.ch/dok/A5261705

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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.
Faculties and Departments:11 Rektorat und Verwaltung > Vizerektorat Forschung
UniBasel Contributors:Meier-Abt, Peter J.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Williams and Wilkins
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2012 14:24
Deposited On:22 Mar 2012 13:37

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