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Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure

Drug Disposition, Eli Lilly and Company, Indianapolis, IN 46278, USA
Current affiliation: Quintiles, Inc., Plainfield, IN 46241, USA
Author to whom correspondence should be addressed.
Pharmaceutics 2013, 5(2), 261-276;
Received: 19 February 2013 / Revised: 26 April 2013 / Accepted: 2 May 2013 / Published: 8 May 2013
(This article belongs to the Special Issue Prodrugs)
PDF [353 KB, uploaded 8 May 2013]


Gemcitabine is an intravenously administered nucleoside analog chemotherapeutic agent. The ability to deliver this agent as an oral drug would allow greater flexibility of administration and patient convenience; however, attempts have been fraught with high first-pass metabolism and potential intestinal toxicity. Alternatively, an amide prodrug of gemcitabine (LY2334737) was discovered, which is able to avoid the extensive first-pass metabolism that occurs following administration of gemcitabine. Preclinical in vitro and in vivo experiments were conducted to evaluate the hydrolysis and pharmacokinetics of LY2334737 and its downstream metabolites. In mice, rats, and dogs, the prodrug is absorbed largely intact across the intestinal epithelium and delivers LY2334737 to systemic circulation. The hydrolysis of LY2334737 is relatively slow, resulting in sustained release of gemcitabine in vivo. In vitro experiments identified carboxylesterase 2 (CES2) as a major enzyme involved in the hydrolysis of LY2334737, but with relatively low intrinsic clearance. Following hydrolysis of the prodrug, gemcitabine is cleared predominantly via the formation of its inactive metabolite dFdU. Both biliary and renal excretion was responsible for the elimination of LY2334737 and its metabolites in both mice and dogs. View Full-Text
Keywords: gemcitabine; prodrug; carboxylesterase; CES2 gemcitabine; prodrug; carboxylesterase; CES2

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Wickremsinhe, E.; Bao, J.; Smith, R.; Burton, R.; Dow, S.; Perkins, E. Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure. Pharmaceutics 2013, 5, 261-276.

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