title: O6-benzylguanine in humans: metabolic, pharmacokinetic, and pharmacodynamic findings.
abstract: OBJECTIVE
  O6-Benzylguanine is a potent inactivator of the DNA-repair protein, O6-alkylguanine-DNA alkyl-transferase (AGT), that enhances sensitivity to nitrosoureas in tumor-cell lines and tumor-bearing animals. The objective of this study was to determine the pharmacokinetics and metabolic fate of O6-Benzylguanine in humans and its effect on AGT activity in peripheral-blood mononuclear cells (PBMCs).
  
  
  METHODS
  Twenty-five cancer patients were treated with O6-Benzylguanine at a dose level of 10, 20, 40, and 80 mg/m2 intravenously (IV) over 1 hour. Plasma and urine samples were collected and analyzed for O6-Benzylguanine and O6-Benzyl-8-oxoguanine concentrations. AGT activity in PBMCs was determined up to 2 weeks postinfusion.
  
  
  RESULTS
  There was no toxicity attributable to O6-Benzylguanine alone at all doses tested. O6-Benzylguanine rapidly disappeared from plasma and was converted to a major metabolite, O6-Benzyl-8-oxoguanine. The half-life of O6-Benzyl-8-oxoguanine increased with dose from 2.8 to 9.2 hours at doses of 10 and 80 mg/m2, respectively. The maximum concentration Cmax and area under the concentration-time curve (AUC) for O6-Benzyl-8-oxoguanine were, respectively, 2.2- and 12- to 29-fold greater than those of O6-Benzylguanine. At all doses, depletion of AGT activity was observed in lymphocytes with a return to baseline by 1 week posttreatment.
  
  
  CONCLUSIONS
  This study demonstrates that administration of O6-Benzylguanine to humans results in a rapid conversion to O6-Benzyl-8-oxoguanine, which follows nonlinear kinetics. Both compounds contribute to an effective depletion of AGT activity in lymphocytes; however, prolonged depletion of AGT activity is likely due primarily to the effect of O6-Benzyl-8-oxoguanine.
authors.affiliation: Section of Hematology-Oncology, Cancer Research Center and Committee on Clinical Pharmacology, The University of Chicago, IL 60637, USA. medolan@mcis.bsd.uchicago.edu
authors.forename: M E
authors.initials: ME
authors.lastname: Dolan
authors.forename: S K
authors.initials: SK
authors.lastname: Roy
authors.forename: A A
authors.initials: AA
authors.lastname: Fasanmade
authors.forename: P R
authors.initials: PR
authors.lastname: Paras
authors.forename: R L
authors.initials: RL
authors.lastname: Schilsky
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000097:blood; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C097065:O(6)-benzyl-8-oxoguanine; C064976:O(6)-benzylguanine; D006147:Guanine; D019883:Alkyl and Aryl Transferases