General Pharmacology Study of Montelukast sodium (MK-476).

Accession number;99A1013022
Title;General Pharmacology Study of Montelukast sodium (MK-476).
Author;ZHAO X-H(Jisseiken Tsukubaken)   ODAGIRI NORIO(Jisseiken Tsukubaken)   CHEN F-J(Jisseiken Tsukubaken)   YAMAMOTO YOSHINORI(Jisseiken Tsukubaken)   TAKAHASHI CHIE(Jisseiken Tsukubaken)   TEZUKA MIKI(Jisseiken Tsukubaken)   TAKASHIMA TOSHIYUKI(Jisseiken Tsukubaken)   SUZUKI JUN(Banyu Pharmaceutical Co., Ltd., Tsukuba Lab.)   NISHIKIBE MASARU(Banyu Pharmaceutical Co., Ltd., Tsukuba Lab.)   
Journal Title;Pharmacometrics
Journal Code:S0617A
ISSN:0300-8533
VOL.57;NO.5/6;PAGE.109-116(1999)
Figure&Table&Reference;FIG.5, TBL.5, REF.4
Pub. Country;Japan
Language;Japanese
Abstract;The general pharmacological effects of montelukast sodium (MK-476) on the central nervous system, autonomic nervous system and smooth muscle, respiratory and cardiovascular systems and digestive system were investigated. With respect to the central nervous system, MK-476 (3, 10 and 100 mg/kg, p.o.) had no effect on hexobarbital-induced anesthesia, pentetrazol- and electric shock-induced convulsions, had no analgesic action in mice and had no effect on spontaneous locomotor activity and body temperature in rats. With respect to the autonomic nervous system and smooth muscle, MK-476 ( 10-6, l0-5 and 10-4 M) alone had no effect on isolated guinea pig ileum. However, MK-476 significantly inhibited ACh-induced contractions in isolated guinea pig ileum at concentrations of 10-5 and 10-4 M and Hist-, 5-HT- and BaCl2-induced contractions in the ileum at a concentration of 10-4 M. With respect to the respiratory and cardiovascular systems, MK-476 (10 mg/kg, i.v.) had no effect on respiration, blood pressure, femoral artery blood flow, heart rate and electrocardiogram (ECG) in anesthetized dogs. With respect to the effect of MK-476 (3, 10 and 100 mg/kg, p.o.) on the digestive system, MK-476 significantly enhanced the gastrointestinal transit of charcoal in mice at a dose of 100 mg/kg. In conclusion, the no-effect dose level (NOEL) of MK-476 was determined to be 10-6 M for ACh-induced contractions in guinea pig ileum, l0-5 M for Hist-, 5-HT- and BaCl2-induced contractions in the ileum, and 10 mg/kg for gastrointestinal transit in mice. The changes observed in these parameters were slight to mild and each NOEL was higher than the intended clinical dose level of 10 mg/man based on the maximum plasma concentration (580-660 ng/ml). Therefore, the changes were not considered to indicate potential adverse effects of MK-476 in clinical use. The highest dose of MK-476 had no effect on the other studied parameters. (author abst.)