title: 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 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 microg/h) or high (32 microg/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.
authors.affiliation: Pfizer Global Research and Development, Ann Arbor, Michigan, USA.
authors.forename: Hani
authors.initials: H
authors.lastname: Zaher
authors.forename: Henriette E
authors.initials: HE
authors.lastname: Meyer zu Schwabedissen
authors.forename: Rommel G
authors.initials: RG
authors.lastname: Tirona
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Cox
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Obert
authors.forename: Nidhi
authors.initials: N
authors.lastname: Agrawal
authors.forename: Joe
authors.initials: J
authors.lastname: Palandra
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Stock
authors.forename: Richard B
authors.initials: RB
authors.lastname: Kim
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ware
mesh_terms: D000818:Animals; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D007275:Injections, Intravenous; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D029362:Organic Anion Transporters, Sodium-Independent / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017035:Pravastatin / Q000378:metabolism* / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D013379:Substrate Specificity / Q000235:genetics
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D029362:Organic Anion Transporters, Sodium-Independent; C498887:Slco1b2 protein, mouse; D017035:Pravastatin; D012293:Rifampin