RT Journal Article
SR Electronic
T1 Targeted Disruption of Murine Organic Anion-Transporting Polypeptide 1b2 (oatp1b2/<em>Slco1b2</em>) Significantly Alters Disposition of Prototypical Drug Substrates Pravastatin and Rifampin
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 320
OP 329
DO 10.1124/mol.108.046458
VO 74
IS 2
A1 Zaher, Hani
A1 zu Schwabedissen, Henriette E. Meyer
A1 Tirona, Rommel G.
A1 Cox, Melissa L.
A1 Obert, Leslie A.
A1 Agrawal, Nidhi
A1 Palandra, Joe
A1 Stock, Jeffrey L.
A1 Kim, Richard B.
A1 Ware, Joseph A.
YR 2008
UL http://molpharm.aspetjournals.org/content/74/2/320.abstract
AB Organic anion-transporting polypeptides (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. It is noteworthy that Slco1b2(-/-) mice were fertile, developed normally, and exhibited no overt phenotypic abnormalities. We confirmed the loss of Oatp1b2 expression in liver using real-time polymerase chain reaction, Western Blot analysis, and immunohistochemistry. Expression of Oatp1a4 and Oatp2b1 but not Oatp1a1 was greater in female Slco1b2(-/-) mice, but expression of other non-OATP transporters did not significantly differ between wild-type and Slco1b2(-/-) male mice. Total bilirubin level was elevated by 2-fold in the Slco1b2(-/-) mice despite the fact 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 (1 mg/kg), a 1.7-fold increase in plasma area under the concentration-time curve (AUC) was observed, whereas the liver-to-plasma ratio was reduced by 5-fold, and nearly 8-fold when assessed at steady-state conditions after 24 h of continuous subcutaneous infusion in Slco1b2(-/-) mice. Likewise, continuous subcutaneous infusion at low (8 μg/h) or high (32 μg/h) dose rates of 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. The American Society for Pharmacology and Experimental Therapeutics