Biotransformation and mass balance of faldaprevir, a hepatitis C NS3/NS4 protease inhibitor in rats.

1. The metabolism, pharmacokinetics, excretion and tissue distribution of a hepatitis C NS3/NS4 protease inhibitor, faldaprevir, were studied in rats following a single 2 mg/kg intravenous or 10 mg/kg oral administration of [C-14]-faldaprevir. 2. Following intravenous dosing, the terminal elimination t(1/2) of plasma radioactivity was 1.75 h (males) and 1.74 h (females). Corresponding AUC(0-infinity), CL and V-ss were 1920 and 1900 ngEq.h/mL, 18.3 and 17.7 mL/min/kg and 2.32 and 2.12 mL/kg for males and females, respectively. 3. After oral dosing, t(1/2) and AUC(0-infinity) for plasma radioactivity were 1.67 and 1.77 h and 11 300 and 17 900 ngEq.h/mL for males and females, respectively. 4. In intact rats, >= 90.17% dose was recovered in feces and only <= 1.08% dose was recovered in urine for both iv and oral doses. In bile cannulated rats, 54.95, 34.32 and 0.27% dose was recovered in feces, bile and urine, respectively. 5. Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism. 6. Radioactivity was rapidly distributed into tissues after the oral dose with peak concentrations of radioactivity in most tissues at 6 h post-dose. The highest levels of radioactivity were observed in liver, lung, kidney, small intestine and adrenal gland.