Pharmacokinetics and metabolism of SL-01, a prodrug of gemcitabine, in rats

Purpose: SL-01, dodecyl-3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl) carbamoyl) pyrazine-2-carboxylate, is a prodrug of gemcitabine. Our previous reports suggested that SL-01 possesses superior bioavailability and Anticancer activity to gemcitabine in mice. In this study, its pharmacokinetics and metabolisms were investigated in rats.

Methods: The pharmacokinetics of SL-01 was studied following intravenous or oral administration of SL-01 to Sprague-Dawley rats. The metabolites profile of SL-01 was further determined in rats receiving intravenous administration of SL-01. Blood samples were analyzed by using LC-MS or LC-MS/MS assay.

Results: Following administration with SL-01 intravenously or orally, SL-01, plasma gemcitabine released from SL-01 as well as the sum of gemcitabine (gemcitabine converted from SL-01 and plasma gemcitabine) exhibited higher values of V z /F and CL z /F, and longer MRT and t 1/2 than those of gemcitabine administered intravenously. The C max of gemcitabine produced by intravenous SL-01 was higher than that of gemcitabine dosed intravenously. The absolute bioavailability for the sum of gemcitabine was 32.2 % for intravenous and 22.2 % for oral administration with SL-01, respectively. After a single intravenous administration, a total of 5 components (M1, M2, M3, M4, and M5) were detected and identified as the metabolites of SL-01 in the plasma of rats. M1 and M2 were formed from the methylation and reduction of SL-01, respectively. Hydrolysis of the amide bond of SL-01 gave M3 and M4. M5 was produced from further dealkylation of M3.

Conclusions: SL-01 displayed improved absorption, good distribution, high clearance, long mean residence time, and moderate bioavailability after administered intravenously or orally to rats. The major metabolic pathways of SL-01 involved methylation, reduction, hydrolysis, and dealkylation. These results suggested that SL-01 acts as a prodrug of gemcitabine in rats.