Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr Rommel Tirona

Abstract

Statins are the first line therapy for treatment and prevention of cardiovascular disease. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, reduce plasma cholesterol levels by inhibiting the rate-limiting step in cholesterol biosynthesis. While statins are well tolerated, up to 15% of patients develop myopathy, manifesting as muscle aches and pain and in rare cases, potentially life-threatening statin-induced rhabdomyolysis. Given that approximately 3 to 4 million Canadians are treated with statins, an estimated 500,000 patients experience associated skeletal muscle side effects that may prevent the continued treatment of hypercholesterolemia. Despite the prevalence of this side effect, little is known regarding the molecular determinants of statin myopathy. Increased systemic statin exposure is linked to risk of developing myopathy, but the role of skeletal muscle exposure and its relevance to muscle toxicity remains to be determined.

Drug transporter proteins are important determinants of drug absorption, tissue exposure and drug elimination. Statins are substrates of multiple drug transporters and require hepatic uptake to exert their cholesterol lowering effect. However, little is known about the role drug transporters have in the skeletal muscle distribution of statins and their toxicity. We aimed to identify drug transporters in skeletal muscle involved in controlling muscle exposure. We found that the uptake transporter OATP2B1 and three novel statin efflux transporters, MRP1, MRP4 and MRP5, are expressed in skeletal muscle. We demonstrate that OATP2B1 sensitizes muscle to toxicity and MRP1 attenuates toxicity of atorvastatin and rosuvastatin in an in vitro skeletal muscle model.

We studied the regulation and function of two transcriptional variants of OATP2B1, demonstrating that these variants had similar function but differential regulation, resulting in ubiquitous expression for OATP2B1 full length form and primarily hepatic expression for the truncated variant. We employed a novel Oatp2b1 knockout mouse model to examine the in vivo role of Oatp2b1 in rosuvastatin disposition. We found that Oatp2b1 does not have a significant effect on rosuvastatin pharmacokinetics but the hepatic exposure was increased in Oatp2b1 knockout mice.

Taken together, these studies further our understanding of the in vitro and in vivo involvement of drug transporters in the context of statin myopathy.


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