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

Abstract

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.

Pharmacokinetics and pharmacogenetics of Gemcitabine as a mainstay in adult and pediatric oncology: an EORTC-PAMM perspective

“…Collectively, these clinical studies indicate that the anti-tumor effect of gemcitabine is schedule dependent and that lower doses can be efficacious. Therefore, it could be advantageous to deliver gemcitabine in a manner where it can achieve prolonged systemic exposure, good efficacy with lower toxicity along with added flexibility of administration and greater patient convenience, such as using an oral formulation [ 48 ]. However, administering gemcitabine orally to patients has been limited by low oral bioavailability, high first-pass clearance, variable systemic exposures during dose escalation studies and observation of gastrointestinal toxicity including nausea, vomiting and diarrhea.…”

Enhanced Antitumor Activity of Monophosphate Ester Prodrugs of Gemcitabine: In Vitro and In Vivo Evaluation

“…It has been shown that human carboxylesterase-2 could hydrolyze LY2334737 to gemcitabine. 16,17 Alternatively, the 5 0 -position substitution of gemcitabine with a fatty acid (such as CP-4126) could lead to better permeability and reduced transport-related drug resistance, although the increased hydrophobicity might decrease the aqueous solubility of this type of prodrugs. 18 In the present study, the 5 0 -position substitution of gemcitabine was achieved with novel ether-lipid-like tail via a phosphate ester bond (Fig.…”

Synthesis and Cytostatic Evaluation of 4-N-Alkanoyl and 4-N-Alkyl Gemcitabine Analogues

“…24 The hydrolyzable amide modifications facilitate a slow release of gemcitabine, increasing its bioavailability and uptake while also providing resistance to enzymatic deamination. 25-32 In 2004, Immordono et al reported the increased anticancer activity of 4- N -stearoyl gemcitabine which was stable in plasma and showed an improved resistance to deamination. 28 Couvreur and Cattel developed the 4- N -squalenoyl gemcitabine prodrug (SQgem) as a chemotherapeutic nanoassembly that accumulates in the cell membranes prior to releasing gemcitabine 26 (Figure 1).…”