Plasma and Cerebrospinal Fluid Pharmacokinetics of 06 - Benzylguanine and Time Course of Peripheral Blood Mononuclear Cell 06 - Methylguanine - DNA Methyltransferase Inhibition in the Nonhuman Primate '

Abstract

06-Benzylguanine (O'BG) enhances the cytotoxicity of the nitrosoureas by irreversibly binding and inhibiting the DNA repair enzyme 06-methyl guanine-DNA methyltransferase (MGMT). The plasma and cerebrospinal fluid (CSF) pharmacokinetics of O6BG and its active metabolite, O6@ benzyl-8-oxoguanine, were studied in a nonhuman primate model after 200 mg/rn2 had been injected i.v. The parent drug and the metabolite were measured with a reverse-phase HPLC assay. A pharmacokinetic model incorporating separate compartments for O'BG and the 06-benzyl-8oxoguanine metabolite, first-order conversion of O6BG to the metabolite, and additional first-order elimination rate constants for each compound, was simultaneously fitted to the parent drug and metabolite plasma concentration time data. Elimination of O6BG from plasma was rapid; it had a half-life of 1.6 h and a clearance of6S mI/minim2.On the basis of the pharmacokinetic model, essentially all of the O6BG was converted to O@-benzyl-8-oxoguanine. The plasma pharmacokinetic profile of the me tabolite differed considerably from that the parent drug. The half-life (14 h) was 10-fold longer and the area under the curve (2420 pM/h) was 11-fold higher than that of O6BG (212 pM/h). The clearance rate of O'-benzyl-8-oxoguanine was 6.4 mI/min/m2. The CSF:plasma ratio was 4.3%forO@BGand36%forO@-benzyI-8-oxoguanine, andthemetabolite area under the curve was 90-fold higher than that of O@BG in CSF. The excellent CSF penetration of the active metabolite provides a rationale for the use of O'BG as a chemosensitizing agent for brain tumors. We also studied the duration of MGMT inhibition in peripheral blood mononu clear cells. By 2 h after a 200 mg/m2 dose of O6BG, >98% of MGMT activity was suppressed, and >95% suppression of enzyme activity per slated at 18 and 48 h after the dose. By 2 weeks after the treatment, MGMT levels had returned to baseline. Persistent high concentrations of the active metabolite appear to provide a pharmacologicalexplanation for the prolonged suppression of MGMT activity.

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Cite this paper

@inproceedings{Berg2006PlasmaAC, title={Plasma and Cerebrospinal Fluid Pharmacokinetics of 06 - Benzylguanine and Time Course of Peripheral Blood Mononuclear Cell 06 - Methylguanine - DNA Methyltransferase Inhibition in the Nonhuman Primate '}, author={Stacey L . Berg and Stanton L . Gerson and Karen S. Godwin and Diane E . Cole and Liii Liu and Frank M . Balls}, year={2006} }