Life Sciences Commons^™

The Role Of Drug Transporters In Statin-Induced Myopathy, Michael J. Knauer

Electronic Thesis and Dissertation Repository

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 …

Statin Transport By Hepatic Organic Anion-Transporting Polypeptides (Oatps), Marianne K. Degorter

Electronic Thesis and Dissertation Repository

Drug transport proteins are important determinants of drug absorption, tissue accumulation, and elimination from the body, and there is growing appreciation for the contribution of altered drug transporter function to interindividual variability in drug response. The organic anion-transporting polypeptides (OATPs/SLCO) are uptake transporters with broad substrate specificity. Notably, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, are commonly prescribed OATP substrates.

The OATP1B subfamily, expressed predominantly in the liver, is of particular importance to statins, which require hepatic entry to exert their low-density lipoprotein cholesterol lowering effect. We aimed to identify molecular determinants of substrate specificity in the …