Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

Dr. Richard B. Kim

Abstract

Membrane transporters are widely recognized for their role in drug disposition in humans. Differences in drug concentration among individuals for drugs used to treat cardiovascular diseases, such as statins and ezetimibe, may result from alteration in hepatic and intestinal transporter function due to genetic, clinical or environmental factors, causing variability in drug efficacy or toxicity.

The closely related uptake transporters organic anion-transporting polypeptides OATP1B3 and OATP1B1, are expressed in human liver sharing numerous drug substrates, including 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, or statins. Recently, a transport-deficient OATP1B1 variant was associated with increased statin exposure and toxicity, however little is known regarding the functional relevance of genetic variation in OATP1B3. We assessed OATP1B3 coding sequence and identified novel polymorphisms; two variants displayed impaired rosuvastatin transport in vitro. OATP1B3 polymorphisms may represent an unrecognized determinant of statin disposition.

The organic solute transporter (OST) αβ is highly expressed in human ileum and plays a key role in bile acid transport from the intestinal lumen into portal blood. However, drug substrates are largely unexplored and the transporter's role in intestinal drug absorption is unknown. We identified four novel drug substrates of OSTαβ, including rosuvastatin and atorvastatin, and characterized an OSTβ variant with impaired transport in vitro. Utilizing biopsy samples, we observed abundant expression in ileum but also duodenum and colon. In Ostα-/- mice, we demonstrated increased rosuvastatin concentration in plasma and liver compared to wild-type, further suggesting a role for OSTαβ in drug transport.

Targeted inhibition of intestinal cholesterol transport by ezetimibe is another cholesterol-lowering approach showing marked interpatient variation, likely resulting from differences in plasma exposure. Evidence suggests a role of drug transporters in circulating ezetimibe concentrations. We observed 67-fold variability in ezetimibe concentration, and 140-fold variability in ezetimibe glucuronide concentration, an active metabolite, in 152 patients taking ezetimibe. We identified age, BMI, gender and concomitant fenofibrate use as major determinants of ezetimibe exposure, whereas transporter polymorphisms were less important predictors; a reduced-function OATP1B3 variant was associated with metabolite-to-parent ratio but not drug level.

These findings illustrate additional mechanistic insights that show the importance of hepatic and intestinal membrane transporters to drug disposition.


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