PHARMACOKINETICS OF O-6-BENZYLGUANINE AND ITS ACTIVE METABOLITE 8-OXO-O-6-BENZYLGUANINE IN PLASMA AND CEREBROSPINAL-FLUID AFTER INTRATHECALADMINISTRATION OF O-6-BENZYLGUANINE IN THE NONHUMAN PRIMATE

O-6-Benzylguanine (O(6)BG) irreversibly inactivates the single-turnove r DNA repair protein alkylguanine-alkyltransferase. Thus, O(6)BG incre ases tumor-cell sensitivity to alkylating agents such as carmustine, l omustine, procarbazine, and temozolomide, We investigated the pharmaco kinetic behavior of O(6)BG and O-6-benzyl-8-oxoguanine (8-oxo-O(6)BG) in cerebrospinal fluid (CSF) and plasma after intraventricular adminis tration of O(6)BG in a nonhuman primate model, In our study, three ani mals received a single l-mg dose of O(6)BG into the lateral ventricle. CSF from the 4(th) ventricle and plasma samples were collected after administration, and O(6)BG and 8-oxo-O(6)BG concentrations were measur ed by high-performance liquid chromatography, Four additional animals received 1 mg of O(6)BG via the intralumbar route weekly for 6 weeks t o assess the feasibility and toxicity of this route of administration. The peak O(6)BG CSF concentration was 412 +/- 86 mu M, the t(1/2) was 0.52 +/- 0.02 h, the clearance was 0.22 +/- 0.01 ml/min, and the area under the concentration-time curve was 319 +/- 15 mu M.h in 4(th) ven tricular CSF, The peak CSF concentration of 8-oxo-O(6)BG in CSF was 1. 9 +/- 0.4 mu M, the t(1/2) was 0.76 +/- 0.03 h, and the area under the concentration-time curve was 5.0 +/- 1.1 mu M.h. Both O(6)BG and 8-ox o-O(6)BG were detected in the plasma 0.5-3 h after intraventricular O( 6)BG administration. The plasma peak concentration of O(6)BG was 0.4 m u M at 30 min, and the concentration was <0.1 mu M by 3 h, The plasma concentration of 8-oxo-O(6)BG was 0.2 mu M at 30 min and 0.6 mu M at 3 h, The animals tolerated the single intraventricular dose and 6 weekl y intralumbar doses of O(6)BG without toxicity. We concluded that intr athecal administration of O(6)BG is well tolerated in the nonhuman pri mate and seems to have a substantial pharmacokinetic advantage over sy stemic administration for meningeal tumors.