Pharmacokinetics of gemcitabine and its amino acid ester prodrug following intravenous and oral administrations in mice

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-valylgemcitabine (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.

Epigenetic regulation of intestinal peptide transporter PEPT1 as a potential strategy for colorectal cancer sensitization

“…PEPT1 is increasingly recognized as an important determinant of drug efficacy and a promising and attractive target in prodrug design 15 , 46 . In this study, our present data suggesting that the mRNA and protein levels of PEPT1 are decreased in CRC.…”

Targeting Pancreatic Ductal Adenocarcinoma (PDAC)

“…However, in vivo pharmacokinetics of one of the most promising derivatives, 5'-L-valyl-gemcitabine, after i.v. and oral administration, revealed a rapid elimination and low oral bioavailability, with an overall systemic exposure to GEM on a par with that obtained with GEM itself [268].…”

Design of an L-Valine-Modified Nanomicelle-Based Drug Delivery System for Overcoming Ocular Surface Barriers

“…Among them, PepT1, a peptide carrier, is important for drug absorption, distribution and clearance in the cornea [19] and can transport dipeptides, tripeptides and α-amino acid esters [20,21]. L-valine (L-Val) is an α-amino acid, and with its dipeptide and ester, it is often used for PepT1 targeting modification in prodrugs or carriers [22][23][24][25].…”