HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

AbstractPURPOSE:
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.
AuthorsKathleen Neville, Susan Blaney, Mark Bernstein, Patrick Thompson, Denise Adams, Alexander Aleksic, Stacey Berg
JournalClinical 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
PMID15297409 (Publication Type: Clinical Trial, Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • O(6)-benzylguanine
  • Guanine
  • O(6)-Methylguanine-DNA Methyltransferase
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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: