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 journalArticle

15 Citations (Scopus)

Abstract

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
Volume43
Issue number8
DOIs
StatePublished - Aug 1 2003

Fingerprint

Pharmacokinetics
DNA Repair Enzymes
Carmustine
8-oxo-O(6)-benzylguanine
O(6)-benzylguanine
Pharmaceutical Preparations
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Tserng, K. Y., Ingalls, S. T., Boczko, E. M., Spiro, T. P., Li, X., Majka, S., ... Hoppel, C. L. (2003). Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-Oxo-O6-benzylguanine. Journal of Clinical Pharmacology, 43(8), 881-893. https://doi.org/10.1177/0091270003256060

Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-Oxo-O6-benzylguanine. / Tserng, Kou Yi; Ingalls, Stephen T.; Boczko, Erik M.; Spiro, Timothy P.; Li, Xiaolin; Majka, Susan; Gerson, Stanton L.; Willson, James K V; Hoppel, Charles L.

In: Journal of Clinical Pharmacology, Vol. 43, No. 8, 01.08.2003, p. 881-893.

Research output: Contribution to journalArticle

Tserng, KY, Ingalls, ST, Boczko, EM, Spiro, TP, Li, X, Majka, S, Gerson, SL, Willson, JKV & Hoppel, CL 2003, 'Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-Oxo-O6-benzylguanine', Journal of Clinical Pharmacology, vol. 43, no. 8, pp. 881-893. https://doi.org/10.1177/0091270003256060
Tserng, Kou Yi ; Ingalls, Stephen T. ; Boczko, Erik M. ; Spiro, Timothy P. ; Li, Xiaolin ; Majka, Susan ; Gerson, Stanton L. ; Willson, James K V ; Hoppel, Charles L. / Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-Oxo-O6-benzylguanine. In: Journal of Clinical Pharmacology. 2003 ; Vol. 43, No. 8. pp. 881-893.
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AU - Spiro, Timothy P.

AU - Li, Xiaolin

AU - Majka, Susan

AU - Gerson, Stanton L.

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