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 [(14)C]-faldaprevir. 2. Following intravenous dosing, the terminal elimination t1/2 of plasma radioactivity was 1.75 h (males) and 1.74 h (females). Corresponding AUC0-∞, CL and Vss 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, t1/2 and AUC0-∞ 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.
Boehringer Ingelheim Pharmaceuticals, Inc. , Ridgefield, CT , USA .
Linzhi
L
Chen
Roger St
RS
George
Stephen H
SH
Norris
Yanping
Y
Mao
Elsy
E
Philip
Li-Quan
LQ
Wang
Diana
D
Wu
Michael J
MJ
Potchoiba
D000284:Administration, Oral; D000621:Aminoisobutyric Acids; D000818:Animals; D001646:Bile; D001711:Biotransformation; D002250:Carbon Radioisotopes / Q000032:analysis; D005243:Feces; D005260:Female; D007275:Injections, Intravenous; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D009842:Oligopeptides / Q000493:pharmacokinetics*; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D011804:Quinolines; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics*; D014556:Urine
D000621:Aminoisobutyric Acids; D002250:Carbon Radioisotopes; D009842:Oligopeptides; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles; C552340:faldaprevir; D011392:Proline; D007930:Leucine
LC/MS; QWBA; metabolite identification; pharmacokinetics; radiolabeled