Interaction of Oatp1b2 expression and nonalcoholic steatohepatitis on pravastatin plasma clearance.
The downregulation of hepatic uptake transporters, including those of the OATP family, are a well known consequence of nonalcoholic steatohepatitis (NASH). Prior studies have shown that the combination of NASH and Oatp1b2 knockout synergistically reduces the clearance of pravastatin (PRAV) in the methionine and choline deficient (MCD) mouse model of NASH, and the current study therefore aimed to determine the impact of NASH and genetic heterozygosity of Oatp1b2 on PRAV clearance, modeling the overlap between the 24% of the human population who are heterozygous for non-functioning OATP1B1, and the ~15% with NASH, potentially placing these people at higher risk of statin-induced myopathy. Therefore, male C57BL/6 wild-type (WT), Oatp1b2+/- (HET), and Oatp1b2-/- (KO) mice were fed either a control (methionine and choline sufficient) or methionine and choline-deficient (MCD) diet to induce NASH. After six weeks of feeding, pravastatin was administered via the carotid artery. Blood and bile samples were collected throughout 90 min after PRAV administration. The concentration of PRAV in plasma, bile, liver, kidney, and muscle was determined by liquid chromatography-tandem mass spectrometry. MCD diet did not alter the plasma AUC values of PRAV in either WT or HET mice. However, the MCD diet increased plasma AUC by 4.4-fold in KO mice. MCD diet and nonfunctional Oatp1b2 synergistically increased not only plasma AUC but also the extrahepatic tissue concentration of pravastatin, whereas the partially decreased function of Oatp1b2 and NASH together were insufficient in significantly altering PRAV pharmacokinetics. These data suggest that a single copy of fully functional OATP1B1 in NASH patients may be sufficient to avoid the increase of pravastatin toxicity.
Animals; Disease Models, Animal; Gene Dosage; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver-Specific Organic Anion Transporter 1; Metabolic Clearance Rate; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Pravastatin
Adverse drug reaction; Nonalcoholic steatohepatitis; Oatp1b2; Pravastatin
Toth, E. L., Clarke, J. D., Csanaky, I., Cherrington, N. J. Interaction of Oatp1b2 expression and nonalcoholic steatohepatitis on pravastatin plasma clearance. Biochemical pharmacology 174, 113780-113780 (2020).