In a crossover study balanced for sex, treatments, and treatment order, we have investigated the pharmacokinetics of diltiazem after single oral doses in 10 healthy middle-aged volunteers. The diltiazem doses employed were 60 mg and 120 mg and contained 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 5.68 +/- 2.62 h (mean +/- SD) after 60 mg and 5.5 +/- 2.22 h after 120 mg. The half-life of the metabolite N-demethyldiltiazem (MA) was similar to or slightly longer than that of diltiazem, whereas the half-life of deacetyldiltiazem (M1) was longer: 9.80 +/- 5.27 h and 10.43 +/- 5.38 h (n = 5). The area under the curve (AUC) of diltiazem increased significantly more than twofold after doubling of the dose, indicating an increased bioavailability, probably because of decreased presystemic elimination. The ratio between the AUCs for metabolites and diltiazem were 0.48 +/- 0.12 and 0.45 +/- 0.06 for MA and 0.16 +/- 0.10 and 0.15 +/- 0.10 for M1 after 60 mg and 120 mg diltiazem. The cumulative excretions of radioactivity within 120 h were 86 +/- 9% and 87 +/- 6%. The tracer was mainly excreted in urine (69 +/- 7% and 72 +/- 6%) and the remaining amounts were excreted in feces.