[In vitro metabolism of an antiallergic agent, emedastine difumarate, in rats and guinea pigs].
In order to clarify the interspecies differences in the metabolism of emedastine difumarate (KG-2413), in vitro metabolism was studied with liver preparations of rats and guinea pigs. The activities of hydroxylase, N-oxidase and N-demethylase, of emedastine were evaluated with liver 9000 x g supernatant and microsomes. As the results, the orders of activities were as follows; 5-hydroxylase greater than or equal to N-oxidase greater than 6-hydroxylase greater than N-demethylase in rats, and N-oxidase much greater than N-demethylase greater than 6-hydroxylase greater than 5-hydroxylase in guinea pigs. Emedastine N-oxide, little excreted into the urine of rats, was largely formed in vitro, so it was assumed that N-oxide reduction was important in vivo. The reductase activity of emedastine N-oxide was evaluated, and compared with N-oxidase activity of emedastine. In rats, the reductase activity was nearly equal to the N-oxidase activity, and relatively high even under aerobic conditions. On the other hand, in guinea pigs, the reductase activity was lower than the N-oxidase activity. It was considered that relative activities of the N-oxidation of tertiary amine in a 1,4-diazepine ring of emedastine and the reduction of N-oxide once formed were one of the factors of interspecies differences of metabolism of emedastine in rats and guinea pigs.
Wada
Y
Y
Pharmaceuticals Research Center, Kanebo, Ltd., Osaka, Japan.
Hamada
T
T
Kawashima
T
T
Awata
N
N
D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics*; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001562:Benzimidazoles; D006634:Histamine H1 Antagonists; C043345:emedastine