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Effects of Diltiazem and Cimetidine on Theophylline Oxidative Metabolism
Author(s) -
Ohashi Kyoichi,
Sakamoto Kouichi,
Sudo Toshiaki,
Tateishi Tomonori,
Fujimura Akio,
Shiga Tsuyoshi,
Ebihara Akio
Publication year - 1993
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1993.tb03925.x
Subject(s) - theophylline , cimetidine , diltiazem , oxidative metabolism , pharmacology , oxidative phosphorylation , medicine , metabolism , chemistry , bronchodilator , asthma , biochemistry , calcium
The effect of diltiazem or cimetidine pretreatment on the inhibition of theophylline oxidative metabolism was investigated in nine healthy male nonsmokers. Diltiazem 60 mg, cimetidine 400 mg, or placebo was given orally three times daily for 3 days in a randomized three‐way crossover manner. Both diltiazem and cimetidine pretreatment decreased the mean theophylline clearance (0.702 on placebo versus 0.641 on diltiazem , P < . 05, and 0.542 mL/minute/kg on cimetidine , P < . 01), resulting in prolonged mean theophylline half‐life (7.56 on placebo versus 8.59 on diltiazem , P < . 05, and 10.08 hours on cimetidine , P < . 01) with no change in volume of distribution. The mean metabolic clearances for three major theophylline metabolites, 1‐methyluric acid (1‐MU), 1,3‐dimethyluric acid (1,3‐DMU), and 3‐methlxanthine (3‐MX), were reduced significantly by cimetidine (28%; P < . 05, 32%; P < . 01, and 33%; P < . 01, respectively). Conversely, diltiazem significantly reduced only the mean metabolic clearance of 1,3‐DMU by 21% ( P < . 05) without changes in that of 1‐MU or 3‐MX. These results suggest that cimetidine inhibited both N‐demethylation and 8‐hydroxylation of theophylline, whereas diltiazem exerted little influence on N‐demethylation in spite of inhibition in 8‐hydroxylation .