Single-dose pharmacokinetics and metabolism of [14C]remofovir in rats and cynomolgus monkeys.
Single-dose pharmacokinetics and metabolism of [(14)C]remofovir was studied in rats and monkeys following intravenous (i.v.) and oral administration (30 mg/kg of body weight). Oral absorption and bioavailability were 29.7 and 5.42% in rats and 65.6 and 19.4% in monkeys, respectively. Following i.v. administration, the elimination half-life for remofovir was 0.7 h in both rats and monkeys. Total body clearance was 5.85 liters/h/kg in rats and 2.60 liters/h/kg in monkeys; apparent volume of distribution was 5.99 liters/kg in rats and 2.70 liters/kg in monkeys. Following oral administration, remofovir was extensively converted to 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and other metabolites in both species. In rats, excretion of total radioactivity in urine accounted for 61.8% of the i.v. dose and 12.9% of the oral dose, while in monkeys it accounted for 43.3% of the i.v. dose and 34.9% of the oral dose. Following i.v. dosing of [(14)C]remofovir, fecal excretion of radioactivity accounted for 37.5% of the dose in rats and 17.4% of the dose in monkeys, indicating significant biliary excretion of the drug in animals. PMEA and metabolite A were the major urinary metabolites in both species after i.v. and oral administration of remofovir.
Lin
Chin-Chung
CC
Research and Development, Valeant Pharmaceuticals International, 3300 Hyland Ave., Costa Mesa, CA 92626, USA. cclin@valeant.com
Xu
Christine
C
Zhu
Nanqun
N
Lourenco
David
D
Yeh
Li-Tain
LT
D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D002250:Carbon Radioisotopes; D006207:Half-Life; D008252:Macaca fascicularis; D008297:Male; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D011355:Prodrugs; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D002250:Carbon Radioisotopes; D009943:Organophosphorus Compounds; D011355:Prodrugs; C497721:pradefovir; D000225:Adenine
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