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) af ter 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)), deac etyl 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 M(A). M1, and M2. The terminal half-lives (t1/2) of Mi and M2 were co nsiderably 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 M6, M2, and then M1. Ex cept for the urinary excretion of M4 there were, no statistically sign ificant differences in any of the pharmacokinetic parameters between t he males and the females. The mean 24 h urinary recovery of M4 was hig her in the males than in the females (P < 0.05). However there were la rge inter-individual variations in the plasma concentrations and urina ry 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-di desmethyl DTZ (M(B)) were identified as two other major urinary metabo lites.