Enoximone is a phosphodiesterase inhibitor, which has been studied extensively for use in the management of patients with moderate-to-severe heart failure. The authors have studied the absorption and disposition kinetics of enoximone and its primary metabolite, enoximone sulfoxide, after both single oral doses of enoximone and at steady-state after short-term chronic oral therapy. A total of ten patients (two female, eight male) with moderate-to-severe heart failure (NYHA class II-IV) were enrolled into the study after giving written informed consent. The plasma levels of enoximone sulfoxide were greater than those of enoximone at all sampling times. The peak enoximone sulfoxide plasma concentrations ranged from 3.5 to 17.3 times the peak enoximone plasma levels for individual patients. The average steady-state plasma concentrations for enoximone were 115 +/- 40 ng/mL and 190 +/- 78 ng/mL for 50 mg every 8 hours and 100 mg every 8 hours dosage regimens, respectively. The absorption and disposition kinetics of enoximone were found to be significantly variable between patients. The authors also evaluated the relationship between dose administered and steady-state plasma levels as well as the relationship between the observed and predicted steady-state plasma levels. The authors found a linear relationship between the dose that was administered and the accrued plasma levels, as well as a good correlation between the predicted and observed steady-state levels. Although these data confirm previous reports that the sulfide metabolite of enoximone accumulates extensively in the plasma during oral therapy, reaching levels much higher than those of enoximone, these data do not support previous suggestions that the disposition of enoximone is nonlinear.