Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates.
Temozolomide is a prodrug that undergoes spontaneous chemical degradation at physiologic pH to form the highly reactive alkylating agent, methyl-triazenyl imidazole carboxamide (MTIC). In clinical trials, temozolomide has activity in gliomas and is approved for recurrent anaplastic astrocytoma. We, therefore, studied the penetration of temozolomide into the cerebrospinal fluid (CSF) as a surrogate for blood-brain barrier penetration in a non-human primate model. Three Rhesus monkeys with indwelling Ommaya reservoirs received 7.5 mg/kg (150 mg/m2) of temozolomide as a 1 h intravenous infusion. Frequent blood and CSF samples were obtained over 24 h, plasma was immediately separated by centrifugation at 4 degrees C, and plasma and CSF samples were acidified with HCl. Temozolomide concentration in plasma and CSF was measured by reverse-phase high-pressure liquid chromatography. Plasma temozolomide concentration peaked 0.5 h after the end of the infusion and was 104 +/- 3 microM. The mean peak CSF temozolomide concentration was 26 +/- 4 microM at 2.5 h. The mean areas under the temozolomide concentration-time curves in plasma and CSF were 392 +/- 18 and 126 +/- 18 microM h, respectively, and the CSF: plasma ratio was 0.33 +/- 0.06. Clearance of temozolomide was 0.116 +/- 0.004 l/kg/h, and the volume of distribution at steady state was 0.254 +/- 0.033 l/kg. In this non-human primate model, temozolomide penetrated readily across the blood-brain barrier. These findings are consistent with the activity of temozolomide in brain tumors.
Patel
Mahendra
M
Pediatric Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20892-1920, USA.
McCully
Cynthia
C
Godwin
Karen
K
Balis
Frank M
FM
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000097:blood* / Q000134:cerebrospinal fluid*; D019540:Area Under Curve; D001812:Blood-Brain Barrier / Q000502:physiology; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood* / Q000134:cerebrospinal fluid*; D006207:Half-Life; D007262:Infusions, Intravenous; D008253:Macaca mulatta; D008297:Male; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide