Inhibition of pentoxifylline clearance by cimetidine.

The effect of cimetidine on the single-dose pharmacokinetics of pentoxifylline and one of its major metabolites, 3,7-dimethyl-1-(5-hydroxyhexyl)xanthine (1), was examined in two groups of male Sprague-Dawley rats (6 rats/group) after the administration of pentoxifylline (1 mg/kg) alone and following a 50 mg/kg iv dose of cimetidine. The addition of cimetidine resulted in a 37% decrease in pentoxifylline clearance (23.8 +/- 7.5 versus 15.0 +/- 3.2 mL/min; p less than 0.03). No changes in the volume of distribution of pentoxifylline or in the total area under the plasma concentration-time curve for 1 were observed with the addition of cimetidine. The mechanism of this metabolic interaction is probably cimetidine-induced inhibition of hepatic microsomal enzymes, which blocks the major excretory pathways for pentoxifylline. Further studies are warranted in humans to determine the existence and clinical significance of this interaction.