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 stea dy-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 cimetid ine. The degree of anticoagulant response produced by warfarin was quantifi ed by the determination of both the prothrombin time and factor-VII clottin g activity. Results: Cimetidine co-administration had no significant effect on the phar macokinetics of the more potent S-warfarin but significantly increased by 2 8% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R-warfarin apparent clearance. Both prothrombin time a nd factor-VII clotting activity displayed considerable inter-subject variab ility and were not significantly affected by concurrent cimetidine treatmen t. The reduction of apparent clearance of li-warfarin by cimetidine was fou nd to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (+/- SD) of R-6-hydrox ywarfarin (31.1 +/- 7.4 ml/h baseline; 18.5 +/- 4.5 ml/h at end of cimetidi ne 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 pharmacok inetics of warfarin by inhibiting the disposition of the less potent R-warf arin in humans. However, this interaction is likely to be of minimal clinic al significance in most patients.