Pharmacokinetics of O6-benzylguanine in rats and its metabolism by rat liver microsomes
Roy, S.K.; Gupta, E.; Dolan, M.E.
Drug Metabolism and Disposition the Biological Fate of Chemicals 23(12): 1394-1399
1995
ISSN/ISBN: 0090-9556 PMID: 8689950 Document Number: 441197
O-6-Benzylguanine is an effective inhibitor of the DNA repair protein, O-6-alkylguanine-DNA alkyltransferase, and enhances the effectiveness of 1,3-bis(2-chloroethyl)-1-nitrosourea in cells in culture and animal tumor models. To prepare O-6-benzylguanine for clinical trials and to determine the availability and disposition of O-6-benzyl-7,8-dihydro-8-oxoguanine (O-6-benzyl-8-oxoguanine), its major metabolite, pharmacokinetic parameters of these compounds were investigated in male Sprague-Dawley rats. Noncompartmental pharmacokinetic parameters were determined following intravenous administration of O-6-benzylguanine or O-6-benzyl-8-oxoguanine in rats. Half-life, clearance, and volume of distribution were respectively, 1.6 hr, 160 ml/hr/kg, and 405 ml/kg for O-6-benzylguanine, and 1.2 hr, 312 ml/hr/kg, and 507 ml/kg for O-6-benzyl-8-oxoguanine. At least 37% of O-6-benzylguanine was converted to O-6-benzyl-8-oxoguanine after administration of O-6-benzylguanine. Renal excretion accounted for 8 and 62% of the administered O-6-benzylguanine and O-6-benzyl-8-oxoguanine, respectively. Administration of phenobarbital to rats before O-6-benzylguanine resulted in a 17- to 19-fold increase in the amount of oxidized product in the urine. Kinetic constants, K-m and V-max were estimated as 19.6 mu-M and 0.02 nmol/min/mg protein and 13.4 mu-M and 0.96 nmol/min/mg protein, for uninduced and induced rat liver microsomes, respectively. The use of inhibitors of cytosolic enzymes, xanthine oxidase, and aldehyde oxidase indicated that aldehyde oxidase is primarily involved in the cytosolic oxidation of O-6-benzylguanine.