Potent and long-lasting action of lafutidine on the human histamine H(2) receptor.
OBJECTIVE
Based on animal models, lafutidine, a novel histamine H(2) receptor (H(2)R) antagonist, is reported to show potent and long-lasting antagonisms of histamine H(2)R-mediated effects. However, no reports have been published concerning its direct interaction with the human H(2)R. This study aims at characterizing its interaction with human H(2)R.


METHODS
Chinese hamster ovary cell lines stably expressing human H(2)Rs were obtained. The dose-dependent effects of lafutidine and famotidine on [(3)H]tiotidine binding and histamine-stimulated cAMP production were analyzed. The effects of preincubation with 2.78 x 10(-7) M of lafutidine or famotidine for 30 min on histamine-dependent cAMP production and [(3)H]tiotidine binding were also examined after 0, 1, 2, 4, and 12 h. This concentration is below the C(max) of lafutidine (10 mg p.o.) and above the C(max) of famotidine (20 mg p.o.).


RESULTS
Lafutidine inhibited [(3)H]tiotidine binding and histamine-stimulated cAMP production as or more potently than famotidine. At higher concentrations lafutidine was more potent than famotidine. In addition, preincubation with 2.78 x 10(-7) M lafutidine, but not with 10(-5) M famotidine, had marked inhibitory effects which persisted as long as after extensive washing.


CONCLUSIONS
Lafutidine shows a potent and long-lasting antagonism on the human H(2)R.
Fukushima
Y
Y
Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Otsuka
H
H
Ishikawa
M
M
Asano
T
T
Anai
M
M
Katsube
T
T
Ogawa
K
K
Kajiwara
T
T
Ohkawa
S
S
Ishikawa
T
T
Omata
M
M
Saitoh
T
T
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002927:Cimetidine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015738:Famotidine / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011970:Receptors, Histamine H2 / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection
D000081:Acetamides; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; D011970:Receptors, Histamine H2; C076948:lafutidine; D015738:Famotidine; D002927:Cimetidine; D000242:Cyclic AMP; C023990:tiotidine