Pharmacokinetics of a novel benzodiazepine partial inverse agonist in the F344 rat, SD rat and B6C3F1 mouse.
1. The pharmacokinetics of a novel benzodiazepine partial inverse agonist (S-8510) were studied in the Fischer 344 (F344) rat and B6C3F1 mouse to obtain information for the planning of carcinogenicity studies. Sprague-Dawley (SD) rats were also included for comparison. 2. Clear non-linear elimination of S-8510 was observed after single oral administration of S-8510 in all animals tested (F344 rat, 1-50 mg/kg; SD rat and B6C3F1 mouse, 1-150 mg/kg). 3. Exposure of S-8510 after single oral administration was in the order F344 rat > B6C3F1 mouse > SD rat. 4. Multiple oral administration to F344 rat and B6C3F1 mouse decreased the exposure to S-8510. 5. These results indicate that it is very important to evaluate pharmacological and toxicological studies based on exposure and to be careful in selecting the species and strains of animal used in toxicology studies.
Nezasa
K
K
Developmental Research Laboratories, Shionogi and Co., Ltd., Osaka, Japan.
Higaki
K
K
Takeuchi
M
M
Yukawa
T
T
Nakano
M
M
D000284:Administration, Oral; D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism*; D018697:Nootropic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013997:Time Factors
D002273:Carcinogens; D018697:Nootropic Agents; C105893:S 8510; D001569:Benzodiazepines