Received for publication May 19, 2008.
Revised May 19, 2008.
Accepted for publication May 20, 2008.

Perspective: Role of the Murine Organic-Anion Transporting Polypeptide 1b2 (Oatp1b2) in Drug Disposition and Hepatoxicity (Relates to article by Zaher et al., FastForward 15 April 08)

Abstract

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. (Pages xxx-xxx), and in a very recent issue of Toxicological Sciences Lu et al. 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 to control mice, providing strong evidence that Oatp1b2 played an important role in the disposition of these drugs. In the accompanying paper, 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.

Key words: Liver transporters, Structure/function/mechanism, Knockout