Species specificity in the blood cholesterol‐lowering effect of YM‐16638

• Published in: British journal of pharmacology Vol. 118; no. 1; pp. 174 - 178
• Main Authors: Goto, Shoichiro, Shimokawa, Teruhiko, Ugawa, Toru, Hisamichi, Nami, Masuyama, Youichi, Iizumi, Yuichi, Sato, Noboru, Takenaka, Toichi, Kodama, Tatsuhiki
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.1996; Nature Publishing
• Subjects: alanine aminotransferase; Alanine Transaminase - blood; Animals; Anticholesteremic Agents - pharmacology; Biological and medical sciences; Body Weight - drug effects; Cholesterol - blood; Cricetinae; General and cellular metabolism. Vitamins; human subjects; hypocholesterolaemic effect; leukotriene antagonist; Liver - anatomy & histology; Liver - drug effects; Liver - metabolism; Macaca fascicularis; Macaca mulatta; Male; Medical sciences; Mesocricetus; Mevalonic Acid - metabolism; Mice; Mice, Inbred ICR; old‐world monkeys; Organ Size - drug effects; Pharmacology. Drug treatments; Rabbits; Rats; Rats, Inbred F344; Saimiri; Species Specificity; Thiadiazoles - pharmacology; YM‐16638; Rat; Rodentia; Monkey; Rabbit; Lipids; Leukotriene D4; Species specificity; Lagomorpha; Cholesterol; Vertebrata; Mammalia; Mouse; Animal; Primates; Antagonist; Hamster; Antilipemic agent; Biological receptor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15382.x

1 . The compound YM‐16638, [[5‐[[3‐(4‐acetyl‐3‐hydroxy‐2‐propylphenoxy)propyl]thio]‐1,3,4‐thiadiazol‐ 2‐yl]thio] acetic acid was developed in a series of in vitro and in vivo studies as a leukotriene D4 receptor antagonist. 2 . In a clinical trial as a leukotriene antagonist drug, this compound was found to have a potent serum cholesterol lowering effect in normolipidaemic healthy male volunteers. 3 . In the present study, we investigated the serum cholesterol lower effect of this compound in various species of experimental animals. 4 . Administration of YM‐16638 did not cause a significant decrease in serum total cholesterol (TC) in mice (up to 200 mg kg−1, body weight per day for 28 days), rats (200 mg kg−1 for 15 days) or rabbits (90 mg kg−1 for 18 days). In hamsters, administration of YM‐16638 orally or by peritoneal injection at 50 mg kg−1 or more daily for 7 days caused a significant decrease in serum TC and the rate of body weight gain. In monkeys, serum TC did not change in YM‐16638‐administered squirrel monkeys (50 mg kg−1 daily for 3 weeks), but a significant decrease in serum TC was observed in cynomolgus monkeys (33% decrease at 30 mg kg−1 for 4 weeks) and rhesus monkeys (27% decrease at 30 mg kg−1 for 3 weeks) without any serious decrease in body weight. These results were consistent with those in a phase I study in human subjects. In contrast, serum alanine aminotransferase (ALT) level decreased in all animals after YM‐16638 treatment. 5 . From these results, we conclude that YM‐16638 has a potent hypocholesterolaemic effect, but that this effect if species‐specific and is only recognized clearly in human subjects and old‐world monkeys.