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

Kou Yi Tserng, Stephen T. Ingalls, Erik M. Boczko, Timothy P. Spiro, Xiaolin Li, Susan Majka, Stanton L. Gerson, James K V Willson, Charles L. Hoppel

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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-Benzylguunine is eliminated rapidly from the plasma compartment in humans (t1/2α and t1/2β 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.

Original languageEnglish (US)
Pages (from-to)881-893
Number of pages13
JournalJournal of clinical pharmacology
Issue number8
StatePublished - Aug 1 2003


  • 8-oxo-O-benzylguanine
  • Cancer
  • O-benzylguanine
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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