Uptake of Enalapril and Expression of Organic Anion Transporting Polypeptide 1 in Zonal, Isolated Rat Hepatocytes

• Published in: Drug metabolism and disposition Vol. 28; no. 7; pp. 801 - 806
• Main Authors: Abu-Zahra, T N, Wolkoff, A W, Kim, R B, Pang, K S
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-07-2000
• Subjects: Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics; Animals; Anion Transport Proteins; Antihypertensive agents; Biological and medical sciences; Cardiovascular system; Carrier Proteins - metabolism; Enalapril - pharmacokinetics; Humans; In Vitro Techniques; Liver - cytology; Liver - metabolism; Male; Medical sciences; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Rat; Liver; Biological transport; Rodentia; Metabolism; In vitro; Uptake; Vertebrata; Organic anion; Mammalia; Enalapril; Hepatocyte; Polypeptide; Animal; ACE inhibitor; Carrier protein
• ISSN: 0090-9556; 1521-009X

Sinusoidal entry is the first obligatory process preceding intracellular drug removal in liver. Transport of the angiotensin
converting enzyme inhibitor enalapril (1–750 μM with [ 3 H]enalapril), a substrate of Oatp1, the sodium-independent organic anion transporting polypeptide 1 cloned from rat liver,
was studied in rat hepatocytes isolated from all zones of the liver (homogeneous) and from enriched periportal (PP) and perivenous
(PV) hepatocytes prepared by collagenase perfusion and zone-selective destruction with digitonin, respectively. Uptake was
linear over 1 min and was concentration-dependent. Transport by the homogeneous hepatocytes (in the presence and absence of
Na + ) and PP and PV cells was described by single saturable components of similar kinetic constants ( K m values of 344–461 μM and V max values of 9.5–11.6 nmol/min/10 6 cells; P > .05, ANOVA). The K m value for enalapril uptake in hepatocytes was of the same order of magnitude compared with that for Oatp1 expressed in HeLa
cells transfected with cDNA-Oatp1 and Western blot analysis revealed similar levels of immunoreactive Oatp1 expression in
PP and PV hepatocytes. However, enalapril was not taken up by Oatp2 nor by the human OATP expressed in recombinant vaccinia
systems.