Synergistic interaction between genetics and disease on pravastatin disposition

John D Clarke; Rhiannon N Hardwick; April D Lake; Andrew J Lickteig; Michael J Goedken; Curtis D Klaassen; Nathan J Cherrington

doi:10.1016/j.jhep.2014.02.021

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Synergistic interaction between genetics and disease on pravastatin disposition

Journal article

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Peer reviewed

Synergistic interaction between genetics and disease on pravastatin disposition

John D Clarke, Rhiannon N Hardwick, April D Lake, Andrew J Lickteig, Michael J Goedken, Curtis D Klaassen and Nathan J Cherrington

Journal of hepatology, Vol.61(1), pp.139-147

07/2014

DOI: https://doi.org/10.1016/j.jhep.2014.02.021

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https://hdl.handle.net/2376/105021

PMCID: PMC4065643

PMID: 24613363

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https://doi.org/10.1016/j.jhep.2014.02.021View

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Abstract

Choline - metabolism

Organic Anion Transporters, Sodium-Independent - genetics

Humans

Hydroxymethylglutaryl-CoA Reductase Inhibitors - blood

Non-alcoholic Fatty Liver Disease - etiology

Male

Organic Anion Transporters - metabolism

Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics

Biological Transport, Active

Organic Anion Transporters - genetics

Pravastatin - adverse effects

Muscles - metabolism

Methionine - deficiency

Organic Anion Transporters, Sodium-Independent - deficiency

Non-alcoholic Fatty Liver Disease - genetics

Liver - metabolism

Mice, Inbred C57BL

Non-alcoholic Fatty Liver Disease - metabolism

Mice, Knockout

Pravastatin - blood

Animals

Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects

Muscles - drug effects

Mice

Pravastatin - pharmacokinetics

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. 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. 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. 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.

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Title: Synergistic interaction between genetics and disease on pravastatin disposition
Creators: John D Clarke - Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States
Rhiannon N Hardwick - Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States
April D Lake - Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States
Andrew J Lickteig - Department of Internal Medicine (Division of Gastroenterology and Hepatology), University of Kansas Medical Center, Kansas City, KS 66160, United States
Michael J Goedken - Department of Pharmacology and Toxicology, Rutgers University, Piscataway, NJ 08854, United States
Curtis D Klaassen - Department of Internal Medicine (Division of Gastroenterology and Hepatology), University of Kansas Medical Center, Kansas City, KS 66160, United States
Nathan J Cherrington - Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, United States. Electronic address: cherrington@pharmacy.arizona.edu
Publication Details: Journal of hepatology, Vol.61(1), pp.139-147
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: Netherlands
Grant note: HD062489 / NICHD NIH HHS R01 AI083927 / NIAID NIH HHS T32 ES007091 / NIEHS NIH HHS ES007091 / NIEHS NIH HHS R01 HD062489 / NICHD NIH HHS AI083927 / NIAID NIH HHS P30 ES006694 / NIEHS NIH HHS ES019487 / NIEHS NIH HHS
Identifiers: 99900546867501842
Language: English
Resource Type: Journal article