The effect of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin in humans.

OBJECTIVE

The interaction of multiple oral doses of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin was investigated in six healthy male volunteers.

METHODS

The subjects were given individually adjusted doses of warfarin to achieve therapeutic levels of prothrombin activity. The established daily maintenance oral dose of warfarin was kept stable throughout the trial and, on study days 8-14, each volunteer received a 800-mg daily dose of cimetidine. The degree of anticoagulant response produced by warfarin was quantified by the determination of both the prothrombin time and factor-VII clotting activity.

RESULTS

Cimetidine co-administration had no significant effect on the pharmacokinetics of the more potent S-warfarin but significantly increased by 28% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R-warfarin apparent clearance. Both prothrombin time and factor-VII clotting activity displayed considerable inter-subject variability and were not significantly affected by concurrent cimetidine treatment. The reduction of apparent clearance of R-warfarin by cimetidine was found to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (+/-SD) of R-6-hydroxywarfarin (31.1+/-7.4 ml/h baseline; 18.5+/-4.5 ml/h at end of cimetidine treatment; P < 0.01), and R-7-hydroxywarfarin (6.9+/-1.3 ml/h baseline; 4.3+/-1.1 ml/h at end of cimetidine treatment; P < 0.01).

CONCLUSION

Cimetidine stereoselectively affects the steady-state pharmacokinetics of warfarin by inhibiting the disposition of the less potent R-warfarin in humans. However, this interaction is likely to be of minimal clinical significance in most patients.