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Pharmacokinetics of O⁶-Benzylguanine (NSC637037) and Its Metabolite, 8-Oxo-O⁶-Benzylguanine

From the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio; Departments of Nutrition, Medicine, Mathematics, and Pharmacology, Case Western Reserve University, Cleveland, Ohio; and Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio.

O⁶-Benzylguanine and its metabolite, 8-oxo-O⁶-benzylguanine, are equally potent inhibitors of the DNA repair enzyme, O⁶-alkylguanine-DNA alkyltransferase. Pharmacokinetic values are derived from cancer patients participating in a phase I trial (10 or 20 mg/m² of O⁶-benzylguanine in a single bolus dose or 10 to 120 mg/m² as a 60-min constant infusion). A two-compartment model fits the plasma concentration versus time profile of O⁶-benzylguanine. O⁶-Benzylguanine is eliminated rapidly from the plasma compartment in humans (t_1/2 and t_1/2ß are 2 ± 2 min and 26 ± 15 min [mean ± SD, n = 7], respectively), and its plasma clearance (513 ± 148 mL/min/m²) is not dose dependent. Metabolite kinetics are evaluated using both a novel approach describing the relationship between O⁶-benzylguanine and 8-oxo-O⁶-benzylguanine and classical metabolite kinetics methods. With increasing doses of O⁶-benzylguanine, the plasma clearance of 8-oxo-O⁶-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.

Key Words: O⁶-benzylguanine • 8-oxo-O⁶-benzylguanine • pharmacokinetics • pharmacodynamics • cancer

Address for reprints: Charles L. Hoppel, MD, VA Medical Center, GRECC 111C(W), 10701 East Boulevard, Cleveland, OH 44106.

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