title: Synergistic interaction between genetics and disease on pravastatin disposition.
abstract: OBJECTIVE
  A genome wide association study and multiple pharmacogenetic studies have implicated the hepatic uptake transporter organic anion transporting polypeptide-1B1 (OATP1B1) in the pharmacokinetics and musculoskeletal toxicity of statin drugs. Other OATP uptake transporters can participate in the transport of pravastatin, partially compensating for the loss of OATP1B1 in patients carrying the polymorphism. Non-alcoholic steatohepatitis (NASH) in humans and in a diet-induced rodent model alter the expression of multiple OATP transporters.
  
  
  METHODS
  To determine how genetic alteration in one Oatp transporter can interact with NASH-associated changes in Oatp expression we measured the disposition of intravenously administered pravastatin in Slco1b2 knockout (Slco1b2(-/-)) and wild-type (WT) mice fed either a control or a methionine and choline deficient (MCD) diet to induce NASH.
  
  
  RESULTS
  Genetic loss of Oatp1b2, the rodent ortholog of human OATP1B transporters, caused a modest increase in pravastatin plasma concentrations in mice with healthy livers. Although a diet-induced model of NASH decreased the expression of multiple hepatic Oatp transporters, it did not alter the disposition of pravastatin compared to WT control mice. In contrast, the combination of NASH-associated decrease in compensatory Oatp transporters and Oatp1b2 genetic loss caused a synergistic increase in plasma area under the curve (AUC) and tissue concentrations in kidney and muscle.
  
  
  CONCLUSIONS
  Our data show that NASH alters the expression of multiple hepatic uptake transporters which, due to overlapping substrate specificity among the OATP transporters, may combine with the pharmacogenetic loss of OATP1B1 to increase the risk of statin-induced adverse drug reactions.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Clarke
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States.
authors.forename: Rhiannon N
authors.initials: RN
authors.lastname: Hardwick
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States.
authors.forename: April D
authors.initials: AD
authors.lastname: Lake
authors.affiliation: Department of Internal Medicine (Division of Gastroenterology and Hepatology), University of Kansas Medical Center, Kansas City, KS 66160, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lickteig
authors.affiliation: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Goedken
authors.affiliation: Department of Internal Medicine (Division of Gastroenterology and Hepatology), University of Kansas Medical Center, Kansas City, KS 66160, United States.
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States. Electronic address: cherrington@pharmacy.arizona.edu.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D002794:Choline / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000172:deficiency* / Q000235:genetics*; D017035:Pravastatin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C498887:Slco1b2 protein, mouse; D008715:Methionine; D017035:Pravastatin; D002794:Choline
keywords: Adverse drug reaction; Myopathy; Non-alcoholic steatohepatitis; Statin