Pharmacokinetics, mass balance, and induction potential of a novel GABA uptake inhibitor, CI-966 HCl, in laboratory animals.
CI-966 exhibits anticonvulsant properties in various animal models. The drug acts by inhibiting synaptic uptake of gamma-aminobutyric acid (GABA). Oral absorption of CI-966 in dogs given 1.39 mg/kg is rapid with a tmax of 0.7 hr. In rats given 5 mg/kg oral, a mean tmax of 4.0 hr was observed. Following iv administration of the same respective doses, elimination t1/2 in dogs and rats averaged 1.2 and 4.5 hr. Absolute oral bioavailability of CI-966 was 100% in both species. Following oral dosing of [14C]CI-966 HCl to dogs, fecal, and urinary excretion accounted for 89% and 2.3% of the 14C dose, respectively. In bile-duct cannulated rats, biliary excretion is the major elimination pathway of radioactivity (75%). Urinary and fecal excretion accounted for 4.1 and 12%, respectively. CI-966 does not induce or inhibit mouse hepatic mixed function oxidases, as determined by hexobarbital sleeping time.
Radulovic
L L
LL
Pharmacokinetics/Drug Metabolism Department, Parke-Davis Pharmaceutical Research Division, Warner-Lamber Company, Ann Arbor, Michigan 48105.
Bockbrader
H N
HN
Chang
T
T
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D018756:GABA Antagonists; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D065607:Cytochrome P-450 Enzyme Inhibitors; D018756:GABA Antagonists; D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C067012:CI 966