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. 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 Lu et al. (Toxicol Sci 103: 35-45, 2008) , 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.
Evers
Raymond
R
Drug Metabolism and Pharmacokinetics, Merck and Co Inc., Rahway, NJ 07065, USA. raymond_evers@merck.com
Chu
Xiao-Yan
XY
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1; D051379:Mice; D029362:Organic Anion Transporters, Sodium-Independent / Q000502:physiology*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; D004364:Pharmaceutical Preparations; C498887:Slco1b2 protein, mouse