INVESTIGATION OF MULTIPLE-DOSE CITALOPRAM ON THE PHARMACOKINETICS ANDPHARMACODYNAMICS OF RACEMIC WARFARIN

Aims An open, controlled, randomized, crossover study was conducted in healthy males to assess the possible occurrence of a pharmacokinetic/ pharmacodynamic interaction between warfarin and the selective seroton in re-uptake inhibitor citalopram. Methods Twelve subjects received a single 25 mg dose of racemic warfarin either alone or on Day 15 of a 2 1-day oral dosing regimen of 40 mg citalopram daily. Blood samples for pharmacokinetic analysis were obtained over a 168 h period after warf arin dosing. The degree of anticoagulation was assessed by the prothro mbin time. Results Citalopram produced no change in the pharmacokineti cs of (R)- and (S)-warfarin, indicating that citalopram does not alter the metabolism of warfarin mediated via CYP1A2, CYP3A4 and CYP2C9. Ci talopram coadministration resulted in a statistically significant incr ease in the maximum prothrombin time (R-max; by 1.6 +/- 3.0 s) and the area under the prothrombin time-time curve (AUC(PT); by 5.0 +/- 5.7%) . The 90% confidence intervals for R-max and AUC(PT) ratios (citalopra m + warfarin/warfarin alone) were 1.01-1.10 and 1.03-1.07, respectivel y. Conclusions The small increase in prothrombin time observed in this study with coadministration of citalopram and warfarin is not conside red to be of importance in the clinical setting.