Pharmacokinetics and absolute bioavailability of diltiazem in humans

Abstract

Six healthy male volunteers received single doses of diltiazem hydrochloride on three occasions separated by at least 10 days. Modes of administration were: 10-minute intravenous infusion of a 20-mg dose; oral administration of 120 mg in solution form; and oral administration of 120 mg as two 60-mg sustained-release tablets. Diltiazem concentrations were measured by electron-capture gas chromatography in multiple plasma samples drawn during the 36 hours after dosage. Following intravenous administration, mean (+/- S.E.) pharmacokinetic variables were: elimination half-life, 11.2 (+/- 2.1) hours; volume of distribution, 11.1 (+/- 3.0) liters/kg; and total clearance, 11.5 (+/- 0.7) ml/min/kg. Oral diltiazem in solution form was rapidly absorbed, with peak plasma levels attained at 38 (+/- 6) minutes after the dose. Absolute systemic availability averaged 44% (+/- 4%). Oral administration of sustained-release tablets yielded, as predicted, slower absorption, with peak plasma concentrations attained at an average of 165 (+/- 22) minutes after dosage. Thus, oral diltiazem is incompletely bioavailable after oral administration, mainly because of first-pass hepatic extraction.

Pharmacokinetics of diltiazem hydrochloride delay-onset sustained-release pellet capsules in healthy volunteers

“…Response to the reported pharmacokinetic parameters of the same multiple oral dose, the present results showed that the time to maximum plasma concentration [t max = (10.39 ± 1.32) h] was prolonged significantly. However, the elimination half-life (t 1/2β = 14.38 ± 0.72 h) remained extending (Lefebvre et al, 1994;Roberts et al, 1991;Ochs et al, 1984).…”

Steady-state pharmacokinetics of diltiazem and hydrochlorothiazide administered alone and in combination

“…Based on preclinical data, desacetyldiltiazem is 25-50% as potent a coronary vasodilator as diltiazem, and the N-desmethyldiltiazem metabolite is about 20% as potent [24,25]. The t 1/2 of orally administered diltiazem averages about 4 h (range: 2 -11 h) in healthy volunteers [21,22]. Again, these published values for diltiazem pharmacokinetic parameters are consistent with the values found in our study, including the large coefficients of variation for C max , C min , and t 1/2 .…”

“…Diltiazem undergoes extensive first-pass metabolism after oral ingestion, with an absolute bioavailability of 40% [20][21][22]. Only 1-3% of an oral dose of diltiazem is excreted unchanged in the urine, while 35% of the dose is recovered as metabolites in the urine [20][21][22].…”

“…Only 1-3% of an oral dose of diltiazem is excreted unchanged in the urine, while 35% of the dose is recovered as metabolites in the urine [20][21][22]. The two primary metabolites, desacetyldiltiazem and N-desmethyldiltiazem, represent 10 and 45%, respec- tively, of the parent drug concentration in plasma [20,21,23]. Based on preclinical data, desacetyldiltiazem is 25-50% as potent a coronary vasodilator as diltiazem, and the N-desmethyldiltiazem metabolite is about 20% as potent [24,25].…”

“…Only 1-3% of an oral dose of diltiazem is excreted unchanged in the urine, while 35% of the dose is recovered as metabolites in the urine [20][21][22]. The two primary metabolites, desacetyldiltiazem and N-desmethyldiltiazem, represent 10 and 45%, respec- tively, of the parent drug concentration in plasma [20,21,23].…”