In summary, DNDI-VL-2098 is not extensively metabolized in preclinical species in vitro and in vivo, and in human microsomes and hepatocytes in vitro. To understand the disposition and excretion pathways of DNDI-VL-2098, studies with 14C labeled DNDI-VL-2098 are planned. DNDI-VL-2098 is a recently identified potent new oral lead compound for Visceral Leishmaniasis that is currently under preclinical development. Convenience of therapy (oral as opposed to parenteral treatment) and patient compliance are important goals for a successful new treatment for VL, particularly because it is endemic in rural areas. As such,

DNDI-VL-2098 represents a major breakthrough for an unmet medical need. The studies described here show that DNDI-VL-2098 possesses excellent preclinical in vitro and in vivo GW786034 molecular weight pharmacokinetic properties in a variety of rodent and non-rodent models. Allometric scaling of these data predicts that the compound will have good pharmacokinetics in humans and the predicted efficacious human doses are amenable to development. The in vitro microsomal intrinsic clearance of DNDI-VL-2098, and its in vivo clearance in animal

models showed a close relationship. selleck In vitro intrinsic clearance was very low in microsomes from all species (<0.6 mL/min/g liver), except in the hamster where it was moderately stable (2.5 mL/min/g liver) Rao et al., 2011. Similarly, the in vivo blood clearance was low in the mouse, rat and dog, and moderate in the hamster. In all of these cases, even if the blood clearance was assumed to entirely reflect only hepatic clearance, DNDI-VL-2098 would be predicted to have a low hepatic extraction ratio (0.10, 0.14 and 0.17 in mouse, rat and dog, respectively), and a moderate extraction ratio

of 0.4 in hamster. These data are consistent with generally good bioavailability of the compound in vivo. The results of the studies suggest that the efficacy of DNDI-VL-2098 seen in vivo in animal models only ( Gupta et al., 2013) results from the potency and pharmacokinetic profile of the parent compound, rather than on any active metabolites. Whether assessed in microsomes, or in hepatocytes, or in blood samples from in vivo dosed animals, DNDI-VL-2098 was metabolically stable and there was consistently no evidence for production of any meaningful metabolite based on LC–MS/MS–UV detection. The samples for in vivo biotransformation were taken following high oral doses leading to high blood concentration of parent drug. The time points selected for assessment (4–8 h post dose) adequately covered the parent compound half-life (1–6 h). Therefore, inadequate analytical sensitivity or early collection points appears unlikely to affect the ability to detect metabolites. Only one, very minor, mono-oxygenation metabolite was detectable in liver microsomes from preclinical species (less than 0.