The Influence of Pretreatment Periods with Diltiazem on Nifedipine Kinetics

Abstract

The effect of durations of diltiazem pretreatment on nifedipine kinetics was evaluated. Eighteen healthy male subjects were randomly allocated to three groups, 6 subjects each, for single doses of 60 mg diltiazem, and 3 days and 6 days with diltiazem 60 mg three times a day. All subjects received 20 mg nifedipine orally on two occasions using a double-blind cross-over, placebo-controlled method. No significant difference on pharmacokinetic parameters of nifedipine without diltiazem were observed among three groups. The single dose with 60 mg diltiazem significantly increased the area under the plasma concentration-time curve (AUC) for nifedipine compared with that in control an average of 35.1% (P < .05) and decreased the total body clearance (CL) an average of 24.0% (P < .05). Three days and 6 days pretreatment with diltiazem 60 mg three times a day significantly increased mean nifedipine AUC to 151.1% (P < .01), 188.0% (P < .05) of control values, and decreased CL to 58.2% (P < .01), 63.9% (P < .05) of control values, respectively. The elimination half-life (t1/2) of nifedipine were significantly prolonged both after 3 days' and after 6 days' pretreatment of diltiazem. These results suggest that diltiazem affects the nifedipine kinetics rapidly and pretreatment duration dependently. A clinically important drug interaction may occur when both drugs are administered simultaneously.

Effect of the Treatment Period With Erythromycin on Cytochrome P450 3A Activity in Humans

“…Diltiazem is also a mechanism‐based inactivator of CYP3A 6 . Ohashi et al 20 studied the effect of a single dose and multiple doses (4 and 7 days of treatment) of diltiazem on the pharmacokinetics of nifedipine. The study showed that diltiazem increased AUC of nifedipine in a duration‐dependent manner.…”

Enhanced effect of triazolam with diltiazem

“…Diltiazem has been reported to affect the pharmacokinetics was increased by about 4 and 3 times, respectively, in comparison with the placebo pretreatment. In our study, of nifedipine depending on the dosage [2], and the period of pretreatment [3]. There was no difference reported the AUC of triazolam was increased by about 2.3 times, and the t 1/2 was prolonged by 1.8 times with diltiazem between 3 days and 6 days of treatment.…”

“…Diltiazem has been reported to inhibit hepatic enzyme metabolism in combination with many therapeutic agents that are metabolized by the CYP3A Methods isozyme, for example, nifedipine, carbamazepine, propranolol and cyclosporine [1]. Ohashi et al [2,3] showed that the Study design metabolism of nifedipine, a substrate for CYP3A4, was affected by the concomitant use of diltiazem, revealing that Seven healthy male volunteers participated in a randomized, double-blind, three-phase crossover study at intervals of at the effect was dose-dependent and was maintained on a plateau during repeated administration. least 1 week.…”

Enhanced cholesterol reduction by simvastatin in diltiazem‐treated patients

“…In in vitro kinetic studies the N ‐desmethyl and N,N ,didesmethyl metabolites of diltiazem are, respectively, 11 and 200 times more potent than the parent drug, as competitive inhibitors of CYP3A4 [ 4]. During chronic therapy these metabolites accumulate in plasma and can reduce the clearance of the parent drug [ 16, 17]. The N ‐demethylated metabolites of diltiazem may possibly contribute to the inhibition of the CYP3A4‐mediated metabolism of simvastatin in vivo.…”