Cargando…

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

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 intest...

Descripción completa

Detalles Bibliográficos
Autores principales: Wickremsinhe, Enaksha, Bao, Jingqi, Smith, Richard, Burton, Richard, Dow, Shannon, Perkins, Everett
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834946/
https://www.ncbi.nlm.nih.gov/pubmed/24300450
http://dx.doi.org/10.3390/pharmaceutics5020261
_version_ 1782292072847376384
author Wickremsinhe, Enaksha
Bao, Jingqi
Smith, Richard
Burton, Richard
Dow, Shannon
Perkins, Everett
author_facet Wickremsinhe, Enaksha
Bao, Jingqi
Smith, Richard
Burton, Richard
Dow, Shannon
Perkins, Everett
author_sort Wickremsinhe, Enaksha
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3834946
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-38349462013-11-21 Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure Wickremsinhe, Enaksha Bao, Jingqi Smith, Richard Burton, Richard Dow, Shannon Perkins, Everett Pharmaceutics Article 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. MDPI 2013-05-08 /pmc/articles/PMC3834946/ /pubmed/24300450 http://dx.doi.org/10.3390/pharmaceutics5020261 Text en © 2013 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
spellingShingle Article
Wickremsinhe, Enaksha
Bao, Jingqi
Smith, Richard
Burton, Richard
Dow, Shannon
Perkins, Everett
Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure
title Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure
title_full Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure
title_fullStr Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure
title_full_unstemmed Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure
title_short Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure
title_sort preclinical absorption, distribution, metabolism, and excretion of an oral amide prodrug of gemcitabine designed to deliver prolonged systemic exposure
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3834946/
https://www.ncbi.nlm.nih.gov/pubmed/24300450
http://dx.doi.org/10.3390/pharmaceutics5020261
work_keys_str_mv AT wickremsinheenaksha preclinicalabsorptiondistributionmetabolismandexcretionofanoralamideprodrugofgemcitabinedesignedtodeliverprolongedsystemicexposure
AT baojingqi preclinicalabsorptiondistributionmetabolismandexcretionofanoralamideprodrugofgemcitabinedesignedtodeliverprolongedsystemicexposure
AT smithrichard preclinicalabsorptiondistributionmetabolismandexcretionofanoralamideprodrugofgemcitabinedesignedtodeliverprolongedsystemicexposure
AT burtonrichard preclinicalabsorptiondistributionmetabolismandexcretionofanoralamideprodrugofgemcitabinedesignedtodeliverprolongedsystemicexposure
AT dowshannon preclinicalabsorptiondistributionmetabolismandexcretionofanoralamideprodrugofgemcitabinedesignedtodeliverprolongedsystemicexposure
AT perkinseverett preclinicalabsorptiondistributionmetabolismandexcretionofanoralamideprodrugofgemcitabinedesignedtodeliverprolongedsystemicexposure