Next Article in Journal / Special Issue
Encapsulation of Hydrocortisone and Mesalazine in Zein Microparticles
Previous Article in Journal
Development of a Novel Lipophilic, Magnetic Nanoparticle for in Vivo Drug Delivery
Previous Article in Special Issue
Design, Synthesis and in Vitro Degradation of a Novel Co-Drug for the Treatment of Psoriasis
Pharmaceutics 2013, 5(2), 261-276; doi:10.3390/pharmaceutics5020261

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

1,* , 1
1 Drug Disposition, Eli Lilly and Company, Indianapolis, IN 46278, USA 2 Current affiliation: Quintiles, Inc., Plainfield, IN 46241, USA
* Author to whom correspondence should be addressed.
Received: 19 February 2013 / Revised: 26 April 2013 / Accepted: 2 May 2013 / Published: 8 May 2013
(This article belongs to the Special Issue Prodrugs)
View Full-Text   |   Download PDF [353 KB, uploaded 8 May 2013]   |   Browse Figures


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.
Keywords: gemcitabine; prodrug; carboxylesterase; CES2 gemcitabine; prodrug; carboxylesterase; CES2
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Share & Cite This Article

Further Mendeley | CiteULike
Export to BibTeX |
MDPI and ACS Style

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.

View more citation formats

Related Articles

Article Metrics

For more information on the journal, click here


Cited By

[Return to top]
Pharmaceutics EISSN 1999-4923 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert