Document Detail

Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-oxo-O6-benzylguanine.
MedLine Citation:
PMID:  12953345     Owner:  NLM     Status:  MEDLINE    
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.
Kou-Yi Tserng; Stephen T Ingalls; Erik M Boczko; Timothy P Spiro; Xiaolin Li; Susan Majka; Stanton L Gerson; James K Willson; Charles L Hoppel
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Publication Detail:
Type:  Clinical Trial; Clinical Trial, Phase I; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of clinical pharmacology     Volume:  43     ISSN:  0091-2700     ISO Abbreviation:  J Clin Pharmacol     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-09-04     Completed Date:  2003-11-10     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0366372     Medline TA:  J Clin Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  881-93     Citation Subset:  IM    
Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Departments of Nutrition, Medicine, Mathematics, and Pharmacology, Case Western Reserve University, Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio, USA.
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MeSH Terms
Antineoplastic Agents, Alkylating / therapeutic use
Carmustine / therapeutic use
Enzyme Inhibitors / metabolism,  pharmacokinetics*,  pharmacology
Guanine / analogs & derivatives*,  blood,  metabolism*,  pharmacokinetics*
Infusions, Intravenous
Metabolic Clearance Rate
Middle Aged
Models, Biological
Neoplasms / drug therapy,  metabolism*
O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors
Grant Support
2 U01 CA62502/CA/NCI NIH HHS; M01 RR-00080-36/RR/NCRR NIH HHS; P30 CA 43703/CA/NCI NIH HHS; R01 CA 75518/CA/NCI NIH HHS
Reg. No./Substance:
0/8-oxo-O(6)-benzylguanine; 0/Antineoplastic Agents, Alkylating; 0/Enzyme Inhibitors; 154-93-8/Carmustine; 73-40-5/Guanine; EC Methyltransferase

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