Biotransformation and mass balance of faldaprevir, a hepatitis C NS3/NS4 protease inhibitor in rats. (November 2014)

• Record Type: Journal Article
• Authors: Chen, Linzhi; George, Roger St.; Norris, Stephen H.; Mao, Yanping; Philip, Elsy; Wang, Li-Quan; Wu, Diana; Potchoiba, Michael J.
• Is Part Of: Xenobiotica. Volume 44:Number 11(2014:Nov.)
• Page Start: 1014
• Page End: 1025
• Publication Date: 2014-11
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.920116
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>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 [¹⁴C]-faldaprevir.</p> <p>2. Following intravenous dosing, the terminal elimination <italic>t</italic>_1/2 of plasma radioactivity was 1.75 h (males) and 1.74 h (females). Corresponding AUC_0–∞, CL and <italic>V</italic>_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.</p> <p>3. After oral dosing, <italic>t</italic>_1/2 and AUC_0–∞ for plasma radioactivity were 1.67 and 1.77 h and 11 300 and 17 900 ngEq · h/mL for males and females, respectively.</p> <p>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.</p> <p>5. Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism.</p> <p>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.</p> </abstract>