title: Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-oxo-O6-benzylguanine.
abstract: 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.
authors.affiliation: 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.
authors.forename: Kou-Yi
authors.initials: KY
authors.lastname: Tserng
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Ingalls
authors.forename: Erik M
authors.initials: EM
authors.lastname: Boczko
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spiro
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Li
authors.forename: Susan
authors.initials: S
authors.lastname: Majka
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: James K
authors.initials: JK
authors.lastname: Willson
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
mesh_terms: D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D002330:Carmustine / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors
chemical_list: C110997:8-oxo-O(6)-benzylguanine; D018906:Antineoplastic Agents, Alkylating; D004791:Enzyme Inhibitors; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine