TY - JOUR T1 - Defining the Role of Gut Bacteria in the Metabolism of Deleobuvir: In Vitro and In Vivo Studies JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1612 LP - 1618 DO - 10.1124/dmd.115.064477 VL - 43 IS - 10 AU - Michelle McCabe AU - Rucha S. Sane AU - Monica Keith-Luzzi AU - Jun Xu AU - Illeaniz King AU - Andrea Whitcher-Johnstone AU - Nicholas Johnstone AU - Donald J. Tweedie AU - Yongmei Li Y1 - 2015/10/01 UR - http://dmd.aspetjournals.org/content/43/10/1612.abstract N2 - Deleobuvir is a potent inhibitor of the hepatitis C virus nonstructural protein 5B polymerase. In humans, deleobuvir underwent extensive reduction to form CD 6168. This metabolite was not formed in vitro in aerobic incubations with human liver microsomes or cytosol. Anaerobic incubations of deleobuvir with rat and human fecal homogenates produced CD 6168. Using these in vitro formation rates, a retrospective analysis was conducted to assess whether the fecal formation of CD 6168 could account for the in vivo levels of this metabolite. The formation of CD 6168 was also investigated using a pseudo-germ free (pGF) rat model, in which gut microbiota were largely eradicated by antibiotic treatment. Plasma exposure (area under the curve from 0 to ∞) of CD 6168 was approximately 9-fold lower in pGF rats (146 ± 64 ng·h/ml) compared with control rats (1,312 ± 649 ng·h/ml). Similarly, in pGF rats, lower levels of CD 6168 (1.5% of the deleobuvir dose) were excreted in feces compared with control rats (42% of the deleobuvir dose). In agreement with these findings, in pGF rats, approximately all of the deleobuvir dose was excreted as deleobuvir into feces (105% of dose), whereas only 26% of the deleobuvir dose was excreted as deleobuvir in control rats. These differences in plasma and excretion profiles between pGF and control rats confirm the role of gut bacteria in the formation of CD 6168. These results underline the importance of evaluating metabolism by gut bacteria and highlight experimental approaches for nonclinical assessment of bacterial metabolism in drug development. ER -