Pharmacokinetics of O(6)-benzylguanine in pediatric patients with central nervous system tumors: a pediatric oncology group study.
OBJECTIVE
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.


METHODS
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.
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Kathleen
K
Neville
Susan
S
Blaney
Mark
M
Bernstein
Patrick
P
Thompson
Denise
D
Adams
Alexander
A
Aleksic
Stacey
S
Berg
D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D004260:DNA Repair / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D006147:Guanine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C064976:O(6)-benzylguanine; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase