Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-oxo-O6-benzylguanine.

Tserng KY, Ingalls ST, Boczko EM, Spiro TP, Li X, Majka S, Gerson SL, Willson JK, Hoppel CL
J Clin Pharmacol. 2003 43 (8): 881-93

PMID: 12953345 · DOI:10.1177/0091270003256060

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 (t1/2 alpha and t1/2 beta 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.

MeSH Terms (15)

Aged Antineoplastic Agents, Alkylating Carmustine Enzyme Inhibitors Female Guanine Half-Life Humans Infusions, Intravenous Male Metabolic Clearance Rate Middle Aged Models, Biological Neoplasms O(6)-Methylguanine-DNA Methyltransferase

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