TY - JOUR T1 - Utility of a Novel Oatp1b2 Knockout Mouse Model for Evaluating the Role of Oatp1b2 in the Hepatic Uptake of Model Compounds JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1840 LP - 1845 DO - 10.1124/dmd.108.020594 VL - 36 IS - 9 AU - Cuiping Chen AU - Jeffery L. Stock AU - Xingrong Liu AU - Jilin Shi AU - Jeffrey W. Van Deusen AU - Debra A. DiMattia AU - Robert G. Dullea AU - Sonia M. de Morais Y1 - 2008/09/01 UR - http://dmd.aspetjournals.org/content/36/9/1840.abstract N2 - We generated the organic anion transporting polypeptide (Oatp) 1b2 knockout (KO) mouse model and assessed its utility to study hepatic uptake using model compounds: cerivastatin, lovastatin acid, pravastatin, simvastatin acid, rifampicin, and rifamycin SV. A selective panel of liver cytochromes P450 (P450s) (Cyp3a11, Cyp3a13, Cyp3a16, Cyp2c29, and Cyp2c39) and transporters [Oatp1b2, Oatp1a1, Oatp1a4, Oatp1a5; organic anion transporter (Oat) 1, Oat2, Oat3; multidrug resistance gene 1 (Mdr1) a, Mdr1b; bile salt export pump, multidrug resistance associated protein (Mrp) 2, Mrp3; breast cancer resistance protein] were measured by reverse transcription-polymerase chain reaction in both KO and wild-type (WT) male mice. Male KO and WT mice received each model compound s.c. at 3 mg/kg. Blood and liver samples were obtained at 0, 0.5, and 2 h postdose and analyzed using liquid chromatography/tandem mass spectrometry. Liver/plasma concentration ratio (Kp,liver) was calculated. Student's t test was used to compare the mRNA and Kp,liver between the KO and WT mice. A similar mRNA expression was observed between the KO and WT for the selected P450s and transporters except for Oatp1b2, for which the level was negligible in the KO but prominent in the WT mice with P < 0.0001. The in vivo results showed a differential effect of Oatp1b2 on hepatic uptake of the model compounds, indicating that Oatp1b2 plays a more significant role in the hepatobiliary disposition of rifampicin and lovastatin than the other compounds tested. This study suggests the Oatp1b2 mouse as a useful in vivo tool to understand drug targeting and disposition in the liver. The American Society for Pharmacology and Experimental Therapeutics ER -