PHARMACOKINETICS OF O-6-BENZYLGUANINE IN RATS AND ITS METABOLISM BY RAT-LIVER MICROSOMES

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 anima l tumor models. To prepare O-6-benzylguanine for clinical trials and t o determine the availability and disposition of O-6-benzyl-7,8-dihydro -8-oxoguanine (O-6-benzyl-8-oxoguanine), its major metebolite, pharmac okinetic parameters of these compounds were investigated in male Sprag ue-Dawley rats, Noncompartmental pharmacokinetic parameters were deter mined following intravenous administration of O-6-benzylguanine or O-6 -benzyl-8-oxoguanine in rats, Half-life, clearance, and volume of dist ribution 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-benzy l-8-oxoguanine. At least 39% of O-6-benzylguanine was converted to O-6 -benzyl-8-oxoguanine after administration of O-6-benzylguanine, Renal excretion accounted for 8 end 62% of the administered O-6-benzylguanin e and O-6-benzyl-8-oxoguanine, respectively, Administration of phenoba rbital to rats before O-6-benzylguanine resulted in a 17- to 19-fold i ncrease in the amount of oxidized product in the urine, Kinetic consta nts, K-M and V-max were estimated as 19.6 mu M and 0.02 nmol/min/mg pr otein and 13.4 mu M and 0.96 nmol/min/mg protein, for uninduced and in duced rat liver microsomes, respectively. The use of inhibitors of cyt osolic enzymes, xanthine oxidase, and aldehyde oxidase indicated that aldehyde oxidase is primarily involved in the cytosolic oxidation of O -6-benzylguanine.