Alteration of Pentoxifylline Pharmacokinetics by Cimetidine

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Abstract
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 < .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 < .05). Apparent oral clearance decreased 21.5% from 1309 ± 304 to 1027 ± 244 mL/min (P < .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.