Pharmacokinetics of O6-benzylguanine and its active metabolite 8-oxo- O6-benzylguanine in plasma and cerebrospinal fluid after intrathecal administration of O6-benzylguanine in the nonhuman primate

Stacey L. Berg, Daryl J. Murry, Cindy L. McCully, Karen Godwin, Frank M. Balis

Research output: Contribution to journalArticle

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Abstract

O6-Benzylguanine (O6BG) irreversibly inactivates the single-turnover DNA repair protein alkylguanine-alkyltransferase. Thus, O6BG increases tumor-cell sensitivity to alkylating agents such as carmustine, lomustine, procarbazine, and temozolomide. We investigated the pharmacokinetic behavior of O6BG and O6-benzyl-8-oxoguanine (8-oxo-O6BG) in cerebrospinal fluid (CSF) and plasma after intraventricular administration of O6BG in a nonhuman primate model. In our study, three animals received a single 1-mg dose of O6BG into the lateral ventricle. CSF from the 4(th) ventricle and plasma samples were collected after administration. and O6BG and 8-oxo-O6BG concentrations were measured by high-performance liquid chromatography. Four additional animals received 1 mg of O6BG via the intralumbar route weekly for 6 weeks to assess the feasibility and toxicity of this route of administration. The peak O6BG CSF concentration was 412 ± 86 μM, 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 ♂ · h in 4(th) ventricular CSF. The peak CSF concentration of 8-oxo-O6BG in CSF was 1.9 ± 0.4 μM, the t(1/2) was 0.76 ± 0.03 h, and the area under the concentration- time curve was 5.0 ± 1.1 μM · h. Both O6BG and 8-oxo-O6BG were detected in the plasma 0.5-3 h after intraventricular O6BG administration. The plasma peak concentration of O6BG was 0.4 μM at 30 min, and the concentration was <0.1 μM by 3 h. The plasma concentration of 8-oxo-O6BG was 0.2 μM at 30 min and 0.6 μM at 3 h. The animals tolerated the single intraventricular dose and 6 weekly intralumbar doses of O6BG without toxicity. We concluded that intrathecal administration of O6BG is well tolerated in the nonhuman primate and seems to have a substantial pharmacokinetic advantage over systemic administration for meningeal tumors.

Original languageEnglish (US)
Pages (from-to)2891-2894
Number of pages4
JournalClinical Cancer Research
Volume4
Issue number11
StatePublished - Nov 1 1998

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Primates
Cerebrospinal Fluid
Pharmacokinetics
8-oxo-O(6)-benzylguanine
O(6)-benzylguanine
temozolomide
Meningeal Neoplasms
Alkyl and Aryl Transferases
Lomustine
Procarbazine
Carmustine
Lateral Ventricles
Alkylating Agents
DNA Repair

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pharmacokinetics of O6-benzylguanine and its active metabolite 8-oxo- O6-benzylguanine in plasma and cerebrospinal fluid after intrathecal administration of O6-benzylguanine in the nonhuman primate. / Berg, Stacey L.; Murry, Daryl J.; McCully, Cindy L.; Godwin, Karen; Balis, Frank M.

In: Clinical Cancer Research, Vol. 4, No. 11, 01.11.1998, p. 2891-2894.

Research output: Contribution to journalArticle

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abstract = "O6-Benzylguanine (O6BG) irreversibly inactivates the single-turnover DNA repair protein alkylguanine-alkyltransferase. Thus, O6BG increases tumor-cell sensitivity to alkylating agents such as carmustine, lomustine, procarbazine, and temozolomide. We investigated the pharmacokinetic behavior of O6BG and O6-benzyl-8-oxoguanine (8-oxo-O6BG) in cerebrospinal fluid (CSF) and plasma after intraventricular administration of O6BG in a nonhuman primate model. In our study, three animals received a single 1-mg dose of O6BG into the lateral ventricle. CSF from the 4(th) ventricle and plasma samples were collected after administration. and O6BG and 8-oxo-O6BG concentrations were measured by high-performance liquid chromatography. Four additional animals received 1 mg of O6BG via the intralumbar route weekly for 6 weeks to assess the feasibility and toxicity of this route of administration. The peak O6BG CSF concentration was 412 ± 86 μM, 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 ♂ · h in 4(th) ventricular CSF. The peak CSF concentration of 8-oxo-O6BG in CSF was 1.9 ± 0.4 μM, the t(1/2) was 0.76 ± 0.03 h, and the area under the concentration- time curve was 5.0 ± 1.1 μM · h. Both O6BG and 8-oxo-O6BG were detected in the plasma 0.5-3 h after intraventricular O6BG administration. The plasma peak concentration of O6BG was 0.4 μM at 30 min, and the concentration was <0.1 μM by 3 h. The plasma concentration of 8-oxo-O6BG was 0.2 μM at 30 min and 0.6 μM at 3 h. The animals tolerated the single intraventricular dose and 6 weekly intralumbar doses of O6BG without toxicity. We concluded that intrathecal administration of O6BG is well tolerated in the nonhuman primate and seems to have a substantial pharmacokinetic advantage over systemic administration for meningeal tumors.",
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T1 - Pharmacokinetics of O6-benzylguanine and its active metabolite 8-oxo- O6-benzylguanine in plasma and cerebrospinal fluid after intrathecal administration of O6-benzylguanine in the nonhuman primate

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AU - Balis, Frank M.

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N2 - O6-Benzylguanine (O6BG) irreversibly inactivates the single-turnover DNA repair protein alkylguanine-alkyltransferase. Thus, O6BG increases tumor-cell sensitivity to alkylating agents such as carmustine, lomustine, procarbazine, and temozolomide. We investigated the pharmacokinetic behavior of O6BG and O6-benzyl-8-oxoguanine (8-oxo-O6BG) in cerebrospinal fluid (CSF) and plasma after intraventricular administration of O6BG in a nonhuman primate model. In our study, three animals received a single 1-mg dose of O6BG into the lateral ventricle. CSF from the 4(th) ventricle and plasma samples were collected after administration. and O6BG and 8-oxo-O6BG concentrations were measured by high-performance liquid chromatography. Four additional animals received 1 mg of O6BG via the intralumbar route weekly for 6 weeks to assess the feasibility and toxicity of this route of administration. The peak O6BG CSF concentration was 412 ± 86 μM, 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 ♂ · h in 4(th) ventricular CSF. The peak CSF concentration of 8-oxo-O6BG in CSF was 1.9 ± 0.4 μM, the t(1/2) was 0.76 ± 0.03 h, and the area under the concentration- time curve was 5.0 ± 1.1 μM · h. Both O6BG and 8-oxo-O6BG were detected in the plasma 0.5-3 h after intraventricular O6BG administration. The plasma peak concentration of O6BG was 0.4 μM at 30 min, and the concentration was <0.1 μM by 3 h. The plasma concentration of 8-oxo-O6BG was 0.2 μM at 30 min and 0.6 μM at 3 h. The animals tolerated the single intraventricular dose and 6 weekly intralumbar doses of O6BG without toxicity. We concluded that intrathecal administration of O6BG is well tolerated in the nonhuman primate and seems to have a substantial pharmacokinetic advantage over systemic administration for meningeal tumors.

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