Pkf. Yeung et al., PHARMACOKINETICS AND METABOLISM OF DILTIAZEM IN HEALTHY-MALES AND FEMALES FOLLOWING A SINGLE ORAL DOSE, European journal of drug metabolism and pharmacokinetics, 18(2), 1993, pp. 199-206
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.