The metabolism and excretion of carbovir, a carbocyclic nucleoside, in the rat.
The metabolism and disposition of carbovir [(1R-cis)-2-amino 1,9-(4-(hydroxymethyl)-2-cyclopenten-1-yl)-6H-purin-6-one], an antiviral agent, was examined in rats using an isolated perfused liver, and in vivo following iv and po administration at two dosing levels. HPLC analysis of perfusate and bile after perfusion of the isolated liver with racemic (+/-)[8-3H]carbovir showed conversion to two major metabolites. The major component in the bile was shown to be a glucuronide conjugate of carbovir. The perfusate contained a single major component that was isolated and identified as the 4'-carboxylic acid derivative. In vivo excretion balance studies were conducted with [8-14C](-)-carbovir using four animals in each dosing group. Following iv administration at 10 mg/kg doses, the majority of the dose (77%) was excreted in the urine. At 60 mg/kg iv dosing, this value dropped to 42% (the remainder appearing in the feces). With po administration at both doses, the bulk of the dose (41-61%) was excreted in the feces. HPLC profiling of the urine showed that in all cases, most of the radioactivity was accounted for as carbovir and the 4'-acid metabolite. This metabolite accounted for up to 25% of the administered dose following 60 mg/kg iv administration, and less than 3% following 10 mg/kg po dosing. A second urinary metabolite accounting for up to 5% of the dose also was seen in all samples. This was isolated and identified as the trans-diastereomer of the 4'-acid (resulting from epimerization at the 4' position).(ABSTRACT TRUNCATED AT 250 WORDS)
Walsh
J S
JS
Department of Drug Metabolism, Glaxo Inc., Research Triangle Park, NC 27709.
Patanella
J E
JE
Unger
S E
SE
Brouwer
K R
KR
Miwa
G T
GT
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003978:Diazomethane; D015224:Dideoxynucleosides / Q000378:metabolism* / Q000493:pharmacokinetics; D005243:Feces / Q000737:chemistry; D005696:Galactosidases / Q000378:metabolism; D005959:Glucosidases / Q000378:metabolism; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D000998:Antiviral Agents; D015224:Dideoxynucleosides; C057503:carbovir; D003978:Diazomethane; D005696:Galactosidases; D005959:Glucosidases