Pharmacokinetics of O6-benzylguanine in rats and its metabolism by rat liver microsomes.
O6-Benzylguanine is an effective inhibitor of the DNA repair protein, O6-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 O6-benzylguanine for clinical trials and to determine the availability and disposition of O6-benzyl-7,8-dihydro-8-oxoguanine (O6-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 O6-benzylguanine or O6-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 O6-benzylguanine, and 1.2 hr, 312 ml/hr/kg, and 507 ml/kg for O6-benzyl-8-oxoguanine. At least 37% of O6-benzylguanine was converted to O6-benzyl-8-oxoguanine after administration of O6-benzylguanine. Renal excretion accounted for 8 and 62% of the administered O6-benzylguanine and O6-benzyl-8-oxoguanine, respectively. Administration of phenobarbital to rats before O6-benzylguanine resulted in a 17- to 19-fold increase in the amount of oxidized product in the urine. Kinetic constants, KM and Vmax were estimated as 19.6 microM and 0.02 nmol/min/mg protein and 13.4 microM 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 O6-benzylguanine.
Roy
S K
SK
Department of Medicine and Cancer Research Center, University of Chicago, IL 60637, USA.
Gupta
E
E
Dolan
M E
ME
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D006207:Half-Life; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000970:Antineoplastic Agents; C097065:O(6)-benzyl-8-oxoguanine; C064976:O(6)-benzylguanine; D006147:Guanine; D010634:Phenobarbital