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Pharmacokinetics of Tiazofurin in the Plasma and Cerebrospinal Fluid of Rhesus Monkeys

Clinical Pharmacology [J. J. G., J. M. C.] and Pediatric [F. M. B., C. M. L., D. G. P.] Branches, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205

The pharmacokinetic disposition of tiazofurin in plasma and cerebrospinal fluid was examined in rhesus monkeys. Tiazofurin was readily detectable in both plasma and cerebrospinal fluid within 20 min of commencement and for 24 h after a short i.v. infusion of the drug. The mean clearance of tiazofurin from plasma was 70 ± 23 (SD) ml/min/sq m after a dose of 100 mg/kg and 106 ± 38 ml/min/sq m after a dose of 500 mg/kg with no evidence of dose dependency. The data for plasma elimination of tiazofurin were fit to a triexponential equation for comparison with data from other species. The t_1/2 was 0.23 h, t_1/2ß was 1.9 to 2.0 h, and t_1/2 was 6.8 to 7.1 h. The ratio of area under the cerebrospinal fluid drug concentration-time curve to the area under the plasma drug concentration-time curve was 0.28, which suggests significant penetration of the blood-brain barrier. These results demonstrate the propensity of tiazofurin to enter the cerebrospinal fluid and, probably, the brain, and suggest a potential role for this agent in the treatment of central nervous system cancer.

¹ To whom requests for reprints should be addressed, at Pediatric Branch, National Cancer Institute, Bldg. 10, Room 13N240, Bethesda, MD 20205.

Received 1/13/84. Revised 10/12/84. Revised 1/11/85. Accepted 1/24/85.