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Plasma and Cerebrospinal Fluid Pharmacokinetics of O⁶-Benzylguanine and Time Course of Peripheral Blood Mononuclear Cell O⁶-Methylguanine-DNA Methyltransferase Inhibition in the Nonhuman Primate¹

Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892 [S. L. B., K. G., D. E. C., F. M. B.]; and Cancer Research Center and Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, Ohio 44106 [S. L. G., L. L.]

O⁶-Benzylguanine (O⁶BG) enhances the cytotoxicity of the nitrosoureas by irreversibly binding and inhibiting the DNA repair enzyme O⁶-methylguanine-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/m² 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 O⁶BG and the O⁶-benzyl-8-oxoguanine 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 of 68 ml/min/m². On the basis of the pharmacokinetic model, essentially all of the O⁶BG was converted to O⁶-benzyl-8-oxoguanine. The plasma pharmacokinetic profile of the metabolite differed considerably from that the parent drug. The half-life (14 h) was 10-fold longer and the area under the curve (2420 µM/h) was 11-fold higher than that of O⁶BG (212 µM/h). The clearance rate of O⁶-benzyl-8-oxoguanine was 6.4 ml/min/m². The CSF:plasma ratio was 4.3% for O⁶BG and 36% for O⁶-benzyl-8-oxoguanine, and the metabolite area under the curve was 90-fold higher than that of O⁶BG in CSF. The excellent CSF penetration of the active metabolite provides a rationale for the use of O⁶BG as a chemosensitizing agent for brain tumors. We also studied the duration of MGMT inhibition in peripheral blood mononuclear cells. By 2 h after a 200 mg/m² dose of O⁶BG, >98% of MGMT activity was suppressed, and >95% suppression of enzyme activity persisted 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 pharmacological explanation for the prolonged suppression of MGMT activity.

¹ S. L. G. and L. L. were supported in part by Grants ROI CA63193, UOI CA57725, and POI CA 51183.

² To whom correspondence should be addressed, at Texas Children's Cancer Center, MC3-3320, 6621 Fannin Street, Houston, TX 77030.

Received 5/18/95. Accepted 8/11/95.

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