PRECLINICAL PHARMACOKINETIC, ANTITUMOR AND TOXICITY STUDIES WITH CL-994 (N-ACETYLDINALINE)

CI-994, a substituted benzamide derivative, is a compound that showed solid tumor selectivity for a variety of solid tumor models compared t o L1210 leukemia. Due to its lack of aqueous solubility, it requires o ral administration. Female B6D2F(1) mice were treated with CI-994 once daily by oral administration of 50 mg/kg for 14 days. Following treat ment mice were evaluated for pharmacodynamic effects as well as the ph armacokinetic behavior of CI-994 and the de-acetylated derivative dina line. Mice samples (plasma, urine, feces) were analyzed using solid ph ase extraction, reverse phase HPLC and ultraviolet detection. The plas ma distribution and elimination half-lives for CI-994 were 51 minutes and 9.4 hours, respectively, on D-1; 31 minutes and 3.4 hours, respect ively on D-14. The apparent plasma distribution and elimination half-l ives for dinaline were 27 minutes and 2.4 hours, respectively, on D-1; 40 minutes and 7.3 hours, respectively on D-14. The CI-994 AUC on D-1 and D-14 were 2879 and 2407 mu g/ml x minutes, respectively; while th e dinaline AUC on D-1 and D-14 were 87 and 92 mu g/ml x minutes, respe ctively. Urinary excretion for CI-994 and dinaline was higher on D-14, while the fecal excretion was the same on both days. The Colon #38 tu mor growth in treated mice was reduced to 22% of that observed in the controls by D-19. The levels of all blood cells were reduced in the tr eated mice when compared to controls and the total WBC was the most af fected (median 38%). Recovery to pretreatment levels occurred quickly following treatment cessation. Phase I evaluation of chronic oral admi nistration of CI-994 is currently ongoing.