title: Effects of serotonin-3 receptor antagonists on cytochrome P450 activities in human liver microsomes.
abstract: The effects of three serotonin-3 (5-HT(3)) receptor antagonists, azasetron, ondansetron, and ramosetron, on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2C9-mediated tolbutamide hydroxylation, CYP2C19-mediated S-mephenytoin 4'-hydroxylation, CYP2D6-mediated debrisoquine 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, CYP3A4-mediated nifedipine oxidation, and CYP3A4-mediated testosterone 6beta-hydroxylation activities in human liver microsomes were compared. Azasetron and ramosetron at a concentration of 1 or 10 muM neither inhibited nor stimulated any of the metabolic activities. On the other hand, ondansetron competitively inhibited CYP1A2 and CYP2D6 activities, and the inhibition constants (K(i)) were 3.2 and 21.0 muM, respectively, which are much higher than the reported plasma concentrations after clinical intravenous or oral dosing. The free fractions of the three 5-HT(3) receptor antagonists in the incubation mixture estimated by ultracentrifugation were more than 68.6%. These results suggest that azasetron, ondansetron, and ramosetron do not cause clinically significant interactions with other drugs that are metabolized by CYPs via the inhibition of metabolism.
authors.affiliation: Post Marketing Product Development, Astellas Pharma Inc, Tokyo, Japan. toshiro.niwa@jp.astellas.com
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niwa
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Miho
authors.initials: M
authors.lastname: Saito
authors.forename: Naoto
authors.initials: N
authors.lastname: Kobayashi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Noda
authors.forename: Akira
authors.initials: A
authors.lastname: Takagi
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology*; D017294:Ondansetron / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D010078:Oxazines; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D017294:Ondansetron; C070671:azasetron; C071315:ramosetron; D003577:Cytochrome P-450 Enzyme System