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Pharmacokinetics of gemcitabine and its amino acid ester prodrug following intravenous and oral administrations in mice.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2020 Oct; Vol. 180, pp. 114127. Date of Electronic Publication: 2020 Jun 27. - Publication Year :
- 2020
-
Abstract
- Gemcitabine is an intravenously administered anti-cancer nucleoside analogue. Systemic exposure following oral administration of gemcitabine is limited by extensive first-pass metabolism via cytidine deaminase (CDA) and potentially by saturation of nucleoside transporter-mediated intestinal uptake. An amino acid ester prodrug of gemcitabine, 5'-l-valyl-gemcitabine (V-Gem), was previously shown to be a substrate of the intestinally expressed peptide transporter 1 (PEPT1) and stable against CDA-mediated metabolism. However, preliminary studies did not evaluate the in vivo oral performance of V-Gem as compared to parent drug. In the present study, we evaluated the pharmacokinetics and in vivo oral absorption of gemcitabine and V-Gem following intravenous and oral administrations in mice. These studies revealed that V-Gem undergoes rapid systemic elimination (half-life < 1 min) and has a low oral bioavailability (<1%). Most importantly, the systemic exposure of gemcitabine was not different following oral administration of equimolar doses of gemcitabine (gemcitabine bioavailability of 18.3%) and V-Gem (gemcitabine bioavailability of 16.7%). Single-pass intestinal perfusions with portal blood sampling in mice revealed that V-Gem undergoes extensive activation in intestinal epithelial cells and that gemcitabine undergoes first-pass metabolism in intestinal epithelial cells. Thus, formulation of gemcitabine as the prodrug V-Gem does not increase systemic gemcitabine exposure following oral dosing, due, in part, to the instability of V-Gem in intestinal epithelial cells.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Subjects :
- Administration, Oral
Animals
Antimetabolites, Antineoplastic administration & dosage
Antimetabolites, Antineoplastic blood
Antimetabolites, Antineoplastic chemistry
Biological Availability
Deoxycytidine administration & dosage
Deoxycytidine blood
Deoxycytidine chemistry
Deoxycytidine pharmacokinetics
Drug Stability
Esters
Injections, Intravenous
Jejunum metabolism
Mice
Mice, Inbred C57BL
Molecular Structure
Prodrugs administration & dosage
Prodrugs chemistry
Gemcitabine
Amino Acids chemistry
Antimetabolites, Antineoplastic pharmacokinetics
Deoxycytidine analogs & derivatives
Prodrugs pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 180
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 32603666
- Full Text :
- https://doi.org/10.1016/j.bcp.2020.114127