title: The effects of diltiazem on hepatic drug metabolizing enzymes in man using antipyrine, trimethadione and debrisoquine as model substrates.
abstract: Six healthy male subjects were given single oral doses of antipyrine (7 mg kg-1), trimethadione (4 mg kg-1) and debrisoquine (10 mg) before and during diltiazem treatment (30 mg three times daily orally for 8 days). Antipyrine clearance decreased from 33.7 +/- 9.1 to 22.5 +/- 4.9 ml min-1 (P less than 0.05, mean +/- s.e. mean) after diltiazem treatment without any significant change in apparent volume of distribution (0.59 +/- 0.06 to 0.60 +/- 0.04 1 kg-1), resulting in an increase in antipyrine elimination half-life from 13.4 +/- 4.8 to 19.7 +/- 3.2 h (P less than 0.05). The formation clearance of antipyrine to 4-hydroxyantipyrine was decreased significantly from 10.8 +/- 2.7 to 6.6 +/- 2.7 ml min-1 (P less than 0.05), while that to 3-hydroxymethylantipyrine and norantipyrine was not altered by diltiazem. The metabolic ratio of debrisoquine (urinary excretion of debrisoquine/4-hydroxydebrisoquine) was increased significantly from 0.70 +/- 0.05 to 1.95 +/- 0.20 (P less than 0.05), while that of trimethadione (serum concentration of dimethadione/trimethadione) was not changed significantly (0.48 +/- 0.08 vs 0.41 +/- 0.06) after diltiazem treatment. Diltiazem selectively inhibits cytochrome P-450 isoenzymes.
authors.affiliation: Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sakai
authors.forename: S
authors.initials: S
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Hamada
authors.forename: S
authors.initials: S
authors.lastname: Iida
authors.forename: H
authors.initials: H
authors.lastname: Akita
authors.forename: E
authors.initials: E
authors.lastname: Tanaka
authors.forename: E
authors.initials: E
authors.lastname: Uchida
authors.forename: H
authors.initials: H
authors.lastname: Yasuhara
mesh_terms: D000328:Adult; D000983:Antipyrine / Q000378:metabolism; D003647:Debrisoquin / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology*; D004114:Dimethadione / Q000097:blood; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D014293:Trimethadione / Q000097:blood / Q000378:metabolism
chemical_list: D004114:Dimethadione; D006899:Mixed Function Oxygenases; D004110:Diltiazem; D014293:Trimethadione; D000983:Antipyrine; D003647:Debrisoquin