Bioavailability of diltiazem as a function of the administered dose

Abstract

Diltiazem undergoes extensive first-pass metabolism; extrapolation from single to repeated administration thus underestimates plasma concentration values. In order to validate the hypothesis of a partially saturable first-pass effect, four single doses of diltiazem (10, 20, 40, and 120 mg) were administered at weekly intervals to eight healthy volunteers. Results showed that: (a) the inter-subject variability was highest at the lowest dose at the highest dose; (b) bioavailability was almost nil in 3 of 8 of the subjects after the administration of the 10 mg dose; (c) the mean bioavailability increased with the dose from 11.8 +/- 2.5 per cent after 10 mg to 28.2 per cent after 120 mg; (d) the elimination half-life was dose-related; (e) the renal excretion of diltiazem increased with the administered dose from 1.0 +/- 0.3 per cent after 10 mg to 3.0 +/- 0.5 per cent after 120 mg; (f) the greatest amounts of circulating metabolites were present after the lowest doses. These results are consistent with a partially saturable first-pass effect for diltiazem.

Voltammetric sensor based on Co3O4/SnO2 nanopowders for determination of diltiazem in tablets and biological fluids

“…The absolute bioavailability of the tablets ranges between 30 and 42 % largely due to presystemic hepatic metabolism [3,4]. After absorption, diltiazem undergoes extensive hepatic metabolism through three major metabolic pathways, N-demethylation, O-deacetylation, and O-demethylation [2][3][4][5]. Diltiazem undergoes hydrolysis to desacetyl diltiazem in acidic solutions and is most stable at pH 5.…”

Semiphysiologically Based Pharmacokinetic Models for the Inhibition of Midazolam Clearance by Diltiazem and Its Major Metabolite

“…In humans, the pharmacokinetic properties of DTZ are characterized by intermediate bioavailability with large variation (25-73%), intermediate to high clearance (11.5-21.3 ml/min/kg), extensive plasma protein binding (77-86%), and a large volume of distribution (3-8 l/kg) (Piepho et al, 1982;Hermann et al, 1983;Bianchetti et al, 1991). DTZ undergoes extensive metabolism, with only 0.1 to 4% of the dose excreted unchanged in the urine (Rovei et al, 1980).…”

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].…”