Abstract | PURPOSE: To report the results of the first pharmacokinetic study in pediatric patients of O(6)-benzylguanine (O(6)BG), which irreversibly inactivates the DNA repair protein alkylguanine- alkyltransferase, thus enhancing the cytotoxicity of nitrosoureas. EXPERIMENTAL DESIGN: As part of a Pediatric Oncology Group Phase I study, 120 mg/m(2) of O(6)BG was administered i.v. over 1 h, before 1,3-bis(2-chloroethyl)-1-nitrosourea administration in children with recurrent or refractory brain tumors. Serial blood samples for plasma pharmacokinetic studies were obtained. Concentrations of O(6)BG and its active metabolite O(6)-benzyl-8-oxoguanine (8-oxo-O(6)BG) were measured by high-performance liquid chromatography. A pharmacokinetic model and additional first-order elimination rate constants for each compound were developed. RESULTS: O(6)BG concentration versus time data were evaluated for 25 patients. The peak concentration of O(6)BG (mean +/- SD) was 11 +/- 4 microm, and the peak concentration of its active metabolite, 8-oxo-O(6)BG, was 35 +/- 10 microm. O(6)BG was rapidly eliminated with a half-life of 85 +/- 140 min, area under the curve of 795 +/- 320 microm. min and clearance of 760 +/- 400 ml/min/m(2). The area under the curve of 8-oxo-O(6)BG when extrapolated to infinity was 22,700 +/- 11,800 microm. min. The clearance and terminal half-life of 8-oxo-O(6)BG were 30 +/- 15 ml/min/m(2) and 360 +/- 220 min, respectively. CONCLUSIONS: There is rapid elimination of O(6)BG after i.v. administration over 1 h. In contrast, the terminal half-life for the active metabolite, 8-oxo-O(6)BG, is 4-fold longer. The pharmacokinetic parameters for O(6)BG and 8-oxo-O(6)BG are similar to those reported previously in adults.
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Authors | Kathleen Neville, Susan Blaney, Mark Bernstein, Patrick Thompson, Denise Adams, Alexander Aleksic, Stacey Berg |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 10
Issue 15
Pg. 5072-5
(Aug 01 2004)
ISSN: 1078-0432 [Print] United States |
PMID | 15297409
(Publication Type: Clinical Trial, Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antineoplastic Agents
- Enzyme Inhibitors
- O(6)-benzylguanine
- Guanine
- O(6)-Methylguanine-DNA Methyltransferase
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Topics |
- Adolescent
- Adult
- Antineoplastic Agents
(administration & dosage, pharmacokinetics)
- Area Under Curve
- Brain Neoplasms
(drug therapy)
- Central Nervous System Neoplasms
(drug therapy)
- Chromatography, High Pressure Liquid
- DNA Repair
(drug effects)
- Dose-Response Relationship, Drug
- Enzyme Inhibitors
(administration & dosage, pharmacokinetics)
- Guanine
(administration & dosage, analogs & derivatives, pharmacokinetics)
- Humans
- Neoplasms
(metabolism)
- O(6)-Methylguanine-DNA Methyltransferase
(antagonists & inhibitors)
- Time Factors
- Treatment Outcome
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