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-'), trimethadione (4 mg kg-') 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 < 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 < 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-' (P < 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 < 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.

Pharmacokinetic and pharmacodynamic interactions between simvastatin and diltiazem in patients with hypercholesterolemia and hypertension

“…Diltiazem is extensively metabolized in the liver into its host metabolites, primarily by deacetylation and demethylation by CYP3A4 in vitro and in vivo (Chaffman and Brogden, 1985;Pichard et al, 1990;Sutton et al, 1997;Jones et al, 1999;Nakagawa and Ishizaki, 2000;Yeo and Yeo, 2001;Kosuge et al, 2001), and probably in part by CYP2C8/9 (Sutton et al, 1997). In addition, diltiazem has been shown to increase the metabolic ratio of debrisoquine (Sakai et al, 1991), suggesting a possible interference with CYP2D6 (Molden et al, 2002). It is possible that the relevant enzyme activity to metabolize diltiazem or its metabolite(s) might be induced by themselves.…”