Metabolism Of Diltiazem Research Articles

Pharmacokinetics and metabolism of diltiazem in healthy males and females following a single oral dose.

Plasma concentrations and urinary excretion of DTZ and its metabolites were determined in 20 healthy volunteers (10 males and 10 females) after they had each been given a single oral 90 mg dose of DTZ. DTZ and six of its metabolites which included N-monodesmethyl DTZ (MA), deacetyl DTZ (M1), deacetyl N-monodesmethyl DTZ (M2), deacetyl O-desmethyl DTZ (M4) and deacetyl DTZ N-oxide (M1NO) and deacetyl N,O-didesmethyl DTZ (M6), were determined by a sensitive and specific HPLC assay. The major metabolites measurable in the plasma of all the volunteers were MA, M1, and M2. The terminal half-lives (t1/2) of M1 and M2 were considerably longer than those of DTZ and MA. Less than 5% of the dose was excreted as unchanged DTZ in the urine over the 24 h period. The major urinary metabolite was MA, followed by M6, M2, and then M1. Except for the urinary excretion of M4 there were no statistically significant differences in any of the pharmacokinetic parameters between the males and the females. The mean 24 h urinary recovery of M4 was higher in the males than in the females (P < 0.05). However there were large inter-individual variations in the plasma concentrations and urinary excretion of DTZ and its metabolites with some parameters differing by more than 20-fold. In addition, O-desmethyl DTZ (Mx) and N,O-didesmethyl DTZ (MB) were identified as two other major urinary metabolites.

Pharmacokinetics of diltiazem and a new analogue, LR-A/113, in the conscious rat.

Pharmacokinetics and metabolism of diltiazem and a new analogue, LR-A/113, have been studied in the rat. Conscious rats, with the jugular vein cannulated, received the compounds by intravenous (3 mg/kg body weight) or oral (50 mg/kg body weight) route. Parent compounds and their N-demethyl and N-deacetyl metabolites were assayed at serial times in blood. Half-life of elimination of diltiazem was significantly shorter than that of LR-A/113, both after oral (37 +/- 9 vs 59 +/- 26 min) and intravenous (29 +/- 12 vs 57 +/- 16 min) administration. N-deacetyl-diltiazem concentrations after oral administration were higher than the parent compound and N-demethyldiltiazem; LR-A/113 blood concentrations were higher than those of its two metabolites. Metabolites were measurable only in traces after intravenous administration. Oral bioavailability was very low, 3.5% for diltiazem and 4.2% for LR-A/113. In conclusion, the substitution of a methyl by an isopropyl group appears to slow in vivo elimination of the analogue of diltiazem, LR-A/113.

Pharmacokinetics and metabolism of diltiazem in rabbits after a single intravenous or single oral administration

Diltiazem (DTZ) 5 mg/kg was given to rabbits either orally (n = 5) or intravenously (n = 6). Plasma concentrations and urinary excretion of DTZ and its metabolites were determined by a high performance liquid chromatography assay (HPLC) for 12 and 48 h post dose, respectively. The results showed that the metabolism and disposition of DTZ in rabbits was similar to that of humans, mean absolute bioavailability (F) of DTZ was approximately 30% and the systemic clearance was 64.0 ml/min/kg. The metabolism of DTZ between the two routes of administration was quantitatively different in that higher plasma concentrations of the metabolites were observed after the intravenous dose. This could be a result of incomplete oral absorption, higher clearance of DTZ and the metabolites during the first pass through the liver (i.e. higher sequential first pass effect), and/or extrahepatic metabolism. On the basis of the plasma concentration-time profiles and urinary excretion of DTZ and its metabolites, it is concluded that the rabbit is a suitable animal model to investigate the kinetics and metabolism of DTZ.

Pharmacokinetics of diltiazem and other calcium entry blockers.

Diltiazem, as well as other calcium entry blockers, is widely prescribed for the treatment of various types of angina. This review summarizes the current state of knowledge of the pharmacokinetics of diltiazem and of two other calcium entry blockers: verapamil and nifedipine. Although unrelated in their chemical structure, these three drugs have common features. They are highly lipophilic and have a large volume of distribution, are mainly cleared by metabolism and undergo an extensive first-pass extraction. On the other hand, as expected from their quite dissimilar structures, they have their own particular kinetic characteristics. For example, metabolism of diltiazem and verapamil gives rise to active metabolites; repeated administration influences the kinetic profile of verapamil but not those of diltiazem and nifedipine. Absorption, distribution and elimination of these three drugs are differently affected by age and pathological conditions. The possible drug interactions involving diltiazem and the other calcium entry blockers are discussed, particularly that with digoxin. Due to its large therapeutic index, there is no need for treatment monitoring of diltiazem. Nevertheless, this procedure may provide useful information for optimizing the dosage regimen of each patient as the pathological condition and drug therapy may be quite complex.