Pharmacokinetics of diltiazem and its metabolites after repeated multiple-dose treatments in healthy volunteers.

In a complete crossover study, balanced for sex and treatment order, we have investigated the pharmacokinetics of diltiazem in 10 healthy middle-aged volunteers. The treatments were 60 mg t.i.d. and 120 mg t.i.d. during 14 days' treatment, with the last dose pulsed with 1.85 MBq [14C]diltiazem. The absorption was rapid and did not differ between treatments. The disposition could be appropriately described using a two-compartment model with terminal half-lives of 6.57 +/- 1.41 h (mean +/- SD) after 60 mg t.i.d. and 5.44 +/- 0.66 h after 120 mg t.i.d. The half-life of the metabolite N-demethyldiltiazem (MA) was similar to that of diltiazem, whereas the half-lives of deacetyldiltiazem (M1) and N-demethyldeacetyldiltiazem (M2) were longer. The plasma concentrations and areas under the curve found after doubling of the dose were not significantly different from dose-adjusted directly proportional estimations. However, the mean concentration of MA in percent of diltiazem concentration was significantly higher at the lower-dose regimen 41 +/- 11% versus 36 +/- 8%, whereas the corresponding values for M1 were 11 +/- 3% versus 11 +/- 4% and for M2 12 +/- 4% versus 12 +/- 6%, respectively. The median cumulative excretions of radioactivity during 120 h were 90 and 93%, respectively. The drug was mainly excreted in urine (73 versus 73%, median), the remaining amounts were eliminated in feces.