Preclinical pharmacokinetic, antitumor and toxicity studies with CI-994 (correction of 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 to L1210 leukemia. Due to its lack of aqueous solubility, it requires oral administration. Female B6D2F1 mice were treated with CI-994 once daily by oral administration of 50 mg/kg for 14 days. Following treatment mice were evaluated for pharmacodynamic effects as well as the pharmacokinetic behavior of CI-994 and the de-acetylated derivative dinaline. Mice samples (plasma, urine, feces) were analyzed using solid phase extraction, reverse phase HPLC and ultraviolet detection. The plasma 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, respectively on D-14. The apparent plasma distribution and elimination half-lives 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 micrograms/ml x minutes, respectively; while the dinaline AUC on D-1 and D-14 were 87 and 92 micrograms/ml x minutes, respectively. 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 tumor 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 treated mice when compared to controls and the total WBC was the most affected (median 38%). Recovery to pretreatment levels occurred quickly following treatment cessation. Phase I evaluation of chronic oral administration of CI-994 is currently ongoing.
Foster
B J
BJ
Karmanos Cancer Institute, Wayne State University School of Medicine, Department of Internal Medicine, Detroit, USA.
Jones
L
L
Wiegand
R
R
LoRusso
P M
PM
Corbett
T H
TH
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity; D019540:Area Under Curve; D001549:Benzamides; D001772:Blood Cell Count; D001853:Bone Marrow / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008657:Metabolic Clearance Rate; D051379:Mice; D010655:Phenylenediamines / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity
D000970:Antineoplastic Agents; D001549:Benzamides; D010655:Phenylenediamines; C045838:dinaline; C081895:tacedinaline