Pharmacokinetics of the Two Major Metabolites of Ethyl Loflazepate (CM6912) in Dogs and Humans. Simulation by a Digital Computer

• Published in: YAKUGAKU ZASSHI Vol. 106; no. 8; pp. 703 - 708
• Main Authors: ITO, MASAYUKI, AIZAWA, KAZUMASA, KOMIYA, IZUMI, MIYAGI, KATSUMI, FUJITA, MASATAKA, UMEMURA, KOSHIRO
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 01-08-1986
• Subjects: Animals; Anti-Anxiety Agents; Benzodiazepines; Benzodiazepinones - metabolism; compartment model; Computer Simulation; Dogs; ethyl loflazepate; Flurazepam - analogs & derivatives; Flurazepam - metabolism; GC-ECD; GC-MS; Humans; Kinetics; metabolite; Models, Biological; pharmacokinetics
• ISSN: 0031-6903; 1347-5231
• DOI: 10.1248/yakushi1947.106.8_703

A linear pharmacokinetic model was developed in order to calculate separately the plasma (or blood) concentrations of CM6913 and CM7116, major metabolites of ethyl loflazepate (CM6912), from the total concentrations of CM6913 and CM7116 (CM6913+CM7116) after the oral administration of CM6912 to dogs and humans. The plasma (or blood) concentrations of CM6913 and CM7116 were elaborately determined by the addition of alkaline solution to inhibit CM6913 degradation. The CM6913 concentration was well simulated by this calculation except for the deviation from one-compartment model in later time after the administration to dogs. The calculated CM7116 concentration was also comparable to the observed concentration. In an early period after the administration, however, the plasma (or blood) concentration of CM7116 was underestimated, especially in humans. The total plasma concentrations of CM6913 and CM7116 are measured routinely because of the rapid degradation of CM6913 in biological samples, hence this model approach will be useful for the separate estimation of the concentrations of the metabolites. In humans, the elimination half-life of CM7116, the most active metabolite of CM6912, was long (132h), which suggests the prolonged effects of CM6912.