Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr. Richard B. Kim

Abstract

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 human OATP1B subfamily in vitro, and found three regions required for transport of a non-statin substrate, cholecystokinin-8, thus improving our understanding of OATP1B transport mechanism. We employed Oatp1b2-/- mice to model reduced OATP1B function in humans, and observed liver-to-plasma ratios of atorvastatin and rosuvastatin were lower in Oatp1b2-/- mice compared with wild-type animals, further emphasizing the importance of this OATP subfamily to hepatic drug uptake.

One challenge to statin therapy is the risk for muscle toxicity associated with elevated systemic statin exposure. We assessed intraindividual variability in statin pharmacokinetics in human subjects, and found a correlation in exposure to atorvastatin and simvastatin, which are both metabolized by cytochrome P450 3A (CYP3A). In contrast, atorvastatin and simvastatin exposure were not correlated with rosuvastatin, a statin that is transported but not significantly metabolized, thus illustrating the interplay between transport and metabolism that influences statin pharmacokinetics.

Though numerous clinical trials have investigated statin effectiveness, interindividual variability in statin pharmacokinetics in a clinical setting is not well understood. We characterized atorvastatin and rosuvastatin concentration in 299 patients at London Health Sciences Center, and observed 45-fold variability. Genetic variants in SLCO1B1 and ABCG2 were associated with rosuvastatin concentration. Atorvastatin concentration was associated with SLCO1B1 variants and with 4β-hydroxycholesterol concentration, a marker of CYP3A activity. Lathosterol, a marker of HMG-CoA reductase function, was not associated with statin concentration in our population.

Taken together, these studies further our understanding of OATP function, both in vivo and in vitro, and the contribution of OATPs to pharmacokinetics and drug response.

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