CENTRAL NERVOUS-SYSTEM TOXICITY AND CEREBROSPINAL-FLUID PHARMACOKINETICS OF INTRAVENTRICULAR 3-[(4-AMINO-2-METHYL-5-PYRIMIDINYL)ETHYL]-1-(2-CHLOROETHYL)-1-NITROSOUREA AND OTHER NITROSOUREAS IN BEAGLES

  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (8) , 3803-3809
Abstract
The CNS toxicity and CSF pharamacokinetics of 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) were determined in beagles and compared to those for 3 other nitrosoureas, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea and chlorozotocin. Of the 4 drugs, ACNU was tolerated best and at doses of 0.2-0.8 mg/wk for 8 consecutive wk. The average half-time for CSF elimination of ACNU was 18 min (range, 12-38 min). This value exceeded the known rate of ACNU decomposition in aqueous solution (28-29 min), implying that the disappearance of ACNU from CSF was due to hydrolytic decomposition and cellular entry and/or transcapillary loss across CNS capillaries. The drug exposure integral (C .times. t) of ACNU in the CSF after a toxic dose low of 0.8 mg in the dogs would achieve the equivalent of in vitro cell kills in excess of 3 logs for rat 9L and human glioma 126 cells. As a potential therapeutic agent for meningeal neoplasia, the major limiting factor may be that the CSF elimination of ACNU is rapid compared to its equilibration time from ventricle to spinal- and cerebral convexity-subarachnoid space. Based on these results, clinical phase I trials of intra-CSF ACNU were instituted.