Pharmacokinetics of Diltiazem and Its Metabolites After Single and Multiple Dosing in Healthy Volunteers

Abstract

The pharmacokinetics of diltiazem in healthy middle-aged volunteers have been investigated after single and multiple doses. Twenty men or women were recruited and were given one single dose and one steady-state treatment in a crossover fashion. Ten were given 60-mg single dose and 60-mg t.i.d. during 14 days and 10 received 120 mg as a single dose and as 120-mg t.i.d. The single dose and the last dose in steady state were pulsed with 1.85 MBq [14C]diltiazem. The absorption was rapid and did not differ between treatments. The disposition could be described using a two-compartment model with terminal half-lives of 6.27 +/- 3.23 h (mean +/- SD) after a single dose of 60 mg diltiazem, 6.05 +/- 1.59 h after 60-mg diltiazem t.i.d., 5.85 +/- 1.04 h after 120-mg diltiazem and 5.90 +/- 0.69 h after 120-mg diltiazem t.i.d. The half-life of the metabolite N-demethyldiltiazem was similar to that of diltiazem whereas the half-lives of the metabolites deacetyldiltiazem and N-demethyldeacetyldiltiazem were longer. The area under the curve of diltiazem in a dosing interval at steady state increased significantly compared with the single dose, indicating an increased bioavailability after repeated dosing, probably because of decreased presystemic elimination. The cumulative excretions of radioactivity in urine within 120 h were 72 +/- 5%, 71 +/- 8%, 71 +/- 6%, and 73 +/- 4%, respectively. The remaining amounts were excreted in feces.