Role of the Murine Organic Anion-Transporting Polypeptide 1b2 (Oatp1b2) in Drug Disposition and Hepatotoxicity
Several members of the organic anion transporting polypeptide (OATP/Oatp) family of uptake transporters are expressed in the hepatocyte sinusoidal membrane in humans and preclinical species. The mouse liver specific Oatp is Oatp1b2, and the human homologs most closely related are OATP1B1 and 1B3. Th...
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Veröffentlicht in: | Molecular pharmacology 2008-08, Vol.74 (2), p.309 |
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Sprache: | eng |
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Zusammenfassung: | Several members of the organic anion transporting polypeptide (OATP/Oatp) family of uptake transporters are expressed in the
hepatocyte sinusoidal membrane in humans and preclinical species. The mouse liver specific Oatp is Oatp1b2, and the human
homologs most closely related are OATP1B1 and 1B3. The substrate specificity of these transporters is broad, and the widely
accepted view is that they play an important role in drug disposition. However, direct evidence that OATP/Oatps are important
for drug disposition in vivo has been lacking thus far. In this issue of Molecular Pharmacology , Zaher et al. ( p. 320 ), along with
, report on the characterization of mice with a targeted disruption of the organic anion transporting polypeptide Oatp1b2.
The Oatp1b2(-/-) mice were viable and fertile and did not demonstrate obvious phenotypic abnormalities. Zaher et al. performed
a pharmacokinetic analysis with the human OATP1B1 and -1B3 substrates rifampicin and pravastatin and demonstrated a reduced
liver-to-plasma ratio for these drugs in knockout compared with control mice, providing strong evidence that Oatp1b2 played
an important role in the disposition of these drugs. Lu et al. found that the Oatp1b2(-/-) mice were completely resistant
to hepatoxicity induced by phalloidin and microcystin-LR. Taken together, these data illustrate that Oatp1b2(-/-) mice are
an important new model to investigate the role of this transporter in drug disposition and hepatotoxicity. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.108.048991 |