The third generation camptothecin analog, AR-67, is undergoing early phase clinical trials as a chemotherapeutic agent. Like all camptothecins it undergoes pH dependent reversible hydrolysis between the lipophilic lactone and the hydrophilic carboxylate. The physicochemical differences between the lactone and carboxylate could potentially give rise to differences in transport across and/or entry into cells. In vitro studies indicated reduced intracellular accumulation and/or apical to basolateral transport of AR-67 lactone in P-gp and/or BCRP overexpressing MDCKII cells and increased cellular uptake of carboxylate in OATP1B1 and OATP1B3 overexpressing HeLa-pIRESneo cells. Pharmacokinetic studies were conducted in rats to study the disposition and oral bioavailability of the lactone and carboxylate and to evaluate the extent of the interaction with uptake and efflux transporters. A pharmacokinetic model accounting for interconversion in the plasma was developed and its performance evaluated through simulations and in vivo transporter inhibition studies using GF120918 and rifampin. The model predicted well the likely scenarios to be encountered clinically from pharmacogenetic differences in transporter proteins, drug-drug interactions and organ function alterations. Oral bioavailability studies showed similarity following lactone and carboxylate administration and indicated the significant role ABC transporters play in limiting the oral bioavailability.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:gradschool_diss-1050 |
| Date | 01 January 2010 |
| Creators | Adane, Eyob Debebe |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | University of Kentucky Doctoral Dissertations |
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