Received for publication February 20, 2008.
Revised April 14, 2008.
Accepted for publication April 14, 2008.

Targeted Disruption of Murine Organic Anion-Transporting Polypeptide 1b2 (oatp1b2/Slco1b2) Significantly Alters Disposition of Prototypical Drug Substrates Pravastatin and Rifampin

Abstract

Organic anion transporting polypeptide (OATP) 1B1 and 1B3 are widely acknowledged as important and rate-limiting to the hepatic uptake of many drugs in clinical use. Accordingly, to better understand the in vivo relevance of OATP1B transporters, targeted disruption of murine Slco1b2 gene was carried out. Interestingly, Slco1b2^-/- mice were fertile, developed normally, and did not exhibit any overt phenotypic abnormalities. We confirmed the loss of Oatp1b2 expression in liver using real-time PCR, Western Blot analysis and immunohistochemistry. Oatp1a4 and Oatp2b1, but not Oatp1a1 expression was greater in female Slco1b2^-/- mice, but expression of other non-oatp transporters did not significantly differ between wildtype and Slco1b2^-/- males. Total bilirubin level was elevated by 2-fold in the Slco1b2^-/- mice despite that liver enzymes ALT and AST were normal. Pharmacological characterization was carried out using two prototypical substrates of human OATP1B1 and 1B3, rifampin and pravastatin. After a single intravenous dose of rifampin (1mg/kg), a 1.7-fold increase in plasma AUC was observed while the liver-to-plasma ratio was reduced by 5-fold, and nearly 8-fold when assessed at steady -state conditions after 24 hours of continuous subcutaneous (SC) infusion in Slco1b2^-/- mice. Similarly, continuous SC-infusion at low dose rate (8 µg/hr) or high dose rate (32 µg/hr) pravastatin resulted in a 4-fold lower liver-plasma ratio in the in Slco1b2^-/- mice. This is the first report of altered drug disposition profile in the Slco1b2 knockout mice and suggests the utility of this model for understanding the in vivo role of hepatic OATP transporters in drug disposition.

Key words: Organic anion, Liver transporters

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				R. Evers and X.-Y. Chu Role of the Murine Organic Anion-Transporting Polypeptide 1b2 (Oatp1b2) in Drug Disposition and Hepatotoxicity Mol. Pharmacol., August 1, 2008; 74(2): 309 - 311. [Abstract] [Full Text] [PDF]