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 (M _A), deacetyl DTZ (M ₁), deacetyl N-monodesmethyl DTZ (M ₂), deacetyl O-desmethyl DTZ (M ₄) and deacetyl DTZ N-oxide (M ₁NO) and deacetyl N,O-didesmethyl DTZ (M ₆), were determined by a sensitive and specific HPLC assay. The major metabolites measurable in the plasma of all the volunteers were M _A, M ₁, and M ₂. The terminal half-lives (t _1/2) of M ₁ and M ₂ were considerably longer than those of DTZ and M _A. Less than 5% of the dose was excreted as unchanged DTZ in the urine over the 24 h period. The major urinary metabolite was M _A, followed by M ₆, M ₂, and then M ₁. Except for the urinary excretion of M ₄ 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 M ₄ 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 (M _x) and N,O-didesmethyl DTZ (M _B) were identified as two other major urinary metabolites.