Pharmacokinetics of a novel antiarrhythmic drug, actisomide.
The pharmacokinetics of a novel antiarrhythmic drug, actisomide, were examined in the rat, dog, monkey, and human. The terminal half-life of actisomide was similar (1.15-1.89 hr) across species, regardless of dose. The total plasma clearance was higher in the monkey (13.5-16.4 mL/min/kg) than in the dog (9.01-9.32 mL/min/kg), rat (8.6-9.8 mL/min/kg), or human (6.79 +/- 1.07 mL/min/kg). Excretion of the parent drug was higher in urine than in feces in the dog and rat, whereas in the monkey and human, urinary and fecal excretions of actisomide were similar. In humans, atypical plasma concentration-time curves with double peak concentrations were observed following oral doses. Systemic availability of actisomide was higher in the dog than in the rat, monkey, and human. Further, the systemic availability appeared to increase with dose in the rat and monkey. The species-dependent systemic availability appeared to be due primarily to species-dependent absorption of actisomide, and not to species-dependent first-pass metabolism, biliary excretion, and/or renal elimination. The absorption of actisomide in the rat and its in vitro uptake in CaCo-2 cells were pH dependent. The higher systemic availability of actisomide observed in the dog may be due partly to the higher pH in the gastrointestinal (GI) tract of the dog. However, the pH differences in the GI tract of the different species alone did not appear to be enough to explain the difference in systemic availability of actisomide.
Cook
C S
CS
Department of Drug Metabolism, Searle Research and Development, Skokie, Illinois 60077.
Rozek
L F
LF
Stolzenbach
J
J
Anderson
S
S
Schoenhard
G L
GL
Karim
A
A
D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008253:Macaca mulatta; D008297:Male; D011744:Pyrimidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D013045:Species Specificity
D000889:Anti-Arrhythmia Agents; D011744:Pyrimidinones; C051827:SC 36602