Date of Award

5-2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Molecular Therapeutics and Cell Signaling

Research Advisor

Alex Sparreboom, Ph.D.

Committee

Sharyn Baker, Pharm D., Ph.D. Bernd Meibohm, Ph.D. Lawrence Pfeffer, Ph.D. Phil Potter, Ph.D.

Keywords

Chemotherapy, Pharmacogenetics

Abstract

Cisplatin is the most widely used anticancer agent; however, the cellular pharmacokinetics are poorly understood. Cisplatin is predominantly eliminated through the urine via active secretion and is associated with nephrotoxicity. Currently, prehydration therapy is employed to prevent toxic renal side effects; however it has not been completely ameliorated. The studies described herein aim to determine the mechanism in which cisplatin enters the kidney cell from the blood and how it is subsequently secreted into the urine. Organic cation transporter 2 (OCT2) and ABCC2 are highly expressed in the kidney on the basolateral and apical membrane, respectively. We determined the contribution of OCT2 and ABCC2 to cisplatin transport and toxicity. We also evaluated the contribution of genetic variation in both transporters to cisplatin pharmacokinetics. Our results suggest a prominent role for OCT2 in the cellular accumulation of cisplatin in vivo and in vitro, whereas, ABCC2 may only play a limited role in cisplatin pharmacokinetics in conjunction with other ABC transporters. OCT2 also significantly influences cisplatin induced nephrotoxicity indicating a potential for new preventative strategies to circumvent toxicity.

DOI

10.21007/etd.cghs.2009.0092

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