RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 1612
OP 1618
DO 10.1124/dmd.115.064477
VO 43
IS 10
A1 Michelle McCabe
A1 Rucha S. Sane
A1 Monica Keith-Luzzi
A1 Jun Xu
A1 Illeaniz King
A1 Andrea Whitcher-Johnstone
A1 Nicholas Johnstone
A1 Donald J. Tweedie
A1 Yongmei Li
YR 2015
UL http://dmd.aspetjournals.org/content/43/10/1612.abstract
AB 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.