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.
Highlights
Gemcitabine (Gemzar®, 2',2'-difluoro-deoxycytidine, dFdC) is a close structural analog of the nucleoside deoxycytidine and has a broad spectrum of anti-tumor activity against several human malignancies including pancreatic [1,2], ovarian [3,4], lung [5,6], breast [7,8], and bladder [9,10]
In order to assess the relative hydrolysis rates in liver and intestine, liver S9 fractions and small intestine homogenates were incubated with LY2334737 and the rate of gemcitabine release measured (Table 1)
The addition of loperamide, a known inhibitor of carboxylesterase 2 (CES2), to human S9 incubations caused an overall decrease in intrinsic clearance with increasing loperamide concentrations (Table 2)
Summary
Gemcitabine (Gemzar®, 2',2'-difluoro-deoxycytidine, dFdC) is a close structural analog of the nucleoside deoxycytidine and has a broad spectrum of anti-tumor activity against several human malignancies including pancreatic [1,2], ovarian [3,4], lung [5,6], breast [7,8], and bladder [9,10]. Increased survival time with improved quality of life was reported compared to the standard dosing regimen in a Phase II study where gemcitabine was infused over 24 h at a 10-fold lower dose (100 mg/m2) to patients with advanced pancreatic adenocarcinoma [20] These clinical studies indicate that the anti-tumor effect of gemcitabine is schedule dependent and that lower doses are efficacious. Preclinical and in vitro data have shown that LY2334737 is more stable to both enzymatic and chemical hydrolysis and leads to improved bioavailability by blocking the site of deamination to its uridine metabolite, reducing its first-pass metabolism [25] This can result in prolonged systemic exposure of gemcitabine compared to both IV and oral administration of gemcitabine. The current studies were conducted to evaluate the pharmacokinetics, metabolism, and excretion of an amide prodrug of gemcitabine that was designed to be dosed orally
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