Pharmacokinetics of O 6 ‐Benzylguanine (NSC637037) and Its Metabolite, 8‐Oxo‐O 6 ‐Benzylguanine

O 6 ‐Benzylguanine and its metabolite, 8‐oxo‐O 6 ‐benzylguanine, are equally potent inhibitors of the DNA repair enzyme, O 6 ‐alkylguanine‐DNA alkyltransferase. Pharmacokinetic values are derived from cancer patients participating in a phase I trial (10 or 20 mg/m 2 of O 6 ‐benzylguanine in a single bolus dose or 10 to 120 mg/m 2 as a 60‐min constant infusion). A two‐compartment model fits the plasma concentration versus time profile of O 6 ‐benzylguanine. O 6 ‐Benzylguanine is eliminated rapidly from the plasma compartment in humans (t 1/2α and t 1/2β are 2 ± 2 min and 26 ± 15 min [mean ± SD, n = 7], respectively), and its plasma clearance (513 ± 148 mL/min/m 2 ) is not dose dependent. Metabolite kinetics are evaluated using both a novel approach describing the relationship between O 6 ‐benzylguanine and 8‐oxo‐O 6 ‐benzylguanine and classical metabolite kinetics methods. With increasing doses of O 6 ‐benzylguanine, the plasma clearance of 8‐oxo‐O 6 ‐benzylguanine decreases, prolonging elimination of the metabolite. This effect is not altered by coadministration of BCNU. The urinary excretion of drug and metabolites is minimal.