Pentoxifylline, recently approved for the treatment of intermittent claudication, is hepatically cleared with a high degree of first-pass metabolism. Subsequently, the effect of cimetidine on pentoxifylline pharmacokinetics was studied in humans. Ten healthy subjects received, in random cross-over fashion, pentoxifylline 400 mg as a controlled-release tablet every 8 hours with and without cimetidine 300 mg four times a day for 7 days. Pentoxifylline and metabolite plasma concentrations over one dosing interval were measured on day 7 of each phase. The unavailability of an immediate-release pentoxifylline dosage form prevented a single dose trial. Cimetidine significantly increased (P less than .05) pentoxifylline area under the curve at steady state 26.2% from 675 +/- 97 (mean +/- SEM) to 852 +/- 108 ng. hr/mL. The average steady-state plasma concentration increased 27.4% from 84 +/- 12 to 107 +/- 14 ng/mL (P less than .05). Apparent oral clearance decreased 21.5% from 1309 +/- 304 to 1027 +/- 244 mL/min (P less than .02). Significant alterations in pentoxifylline metabolite concentrations were also observed. The results of this trial suggest cimetidine elevates pentoxifylline plasma concentrations, presumably by decreasing apparent oral clearance, although a reduction in total body clearance or an increase in gastric absorption could not be ruled out.