Lack of citalopram effect on oral digoxin pharmacokinetics.

The effect of chronic administration of citalopram on the single oral dose pharmacokinetics of digoxin was evaluated in 11 healthy adult subjects in an open, one-way crossover study. Subjects received 1 mg digoxin on day 1. Serial blood samples and total urine were collected over 192 hours, followed by an 11-day washout period. On days 22 through 50, subjects received 40 mg citalopram once daily. On day 43, a single dose of 1 mg digoxin was coadministered; again, serial blood samples and total urine were collected over 192 hours after the digoxin dose. There were no statistically significant differences in any of the digoxin pharmacokinetic parameters (AUC(0-->24), AUC(0-->infinity), Cmax, tmax, t(1/2), CL/F, CLrenal, and Ae(0-->infinity)), and the 90% confidence intervals for treatment differences for the parameters (except for tmax) were all within 80% to 125%. Concomitant digoxin administration did not significantly affect citalopram pharmacokinetics. The treatment was well tolerated by all subjects; no serious adverse events and no clinically significant ECG changes were observed. These data suggest that it is unlikely that concomitantly administered citalopram would have any significant effect on serum digoxin concentrations in patients who are receiving chronic digoxin therapy.

Investigation of multiple dose citalopram on the pharmacokinetics and pharmacodynamics 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 serotonin re-uptake inhibitor citalopram. METHODS: Twelve subjects received a single 25 mg dose of racemic warfarin either alone or on Day 15 of a 21-day oral dosing regimen of 40 mg citalopram daily. Blood samples for pharmacokinetic analysis were obtained over a 168 h period after warfarin dosing. The degree of anticoagulation was assessed by the prothrombin time. RESULTS: Citalopram produced no change in the pharmacokinetics of (R)- and (S)-warfarin, indicating that citalopram does not alter the metabolism of warfarin mediated via CYP1A2, CYP3A4 and CYP2C9. Citalopram coadministration resulted in a statistically significant increase 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 (citalopram + warfarin/warfarin alone) were 1.01-1.10 and 1.03-1.07, respectively. CONCLUSIONS: The small increase in prothrombin time observed in this study with coadministration of citalopram and warfarin is not considered to be of importance in the clinical setting.

Steady-state pharmacokinetics of the enantiomers of citalopram and its metabolites in humans.

The steady-state pharmacokinetics in serum and urine of the enantiomers of citalopram and its metabolites, demethylcitalopram (DCT) and didemethylcitalopram (DDCT), were investigated after multiple doses of rac-citalopram for 21 consecutive days (40 mg per day) to healthy human subjects who were extensive metabolisers of sparteine and mephenytoin. Comparable pharmacokinetic variability was noted for (+)-(S)-, (-)-(R)- and rac-citalopram. Enantiomeric (S/R) serum concentration ratios for citalopram were always less than unity and were constant during the steady-state dosing interval. A modest, but statistically significant, stereoselectivity in the disposition of citalopram and its two main metabolites was observed. Serum levels of the (+)-(S)-enantiomers of citalopram, DCT, and DDCT throughout the steady-state dosing interval investigated were 37 +/- 6%, 42 +/- 3% and 32 +/- 3%, respectively, of their total racemic serum concentrations. The (+)-(S)-enantiomers of citalopram, DCT, and DDCT were eliminated faster than their antipodes. For (-)-(R)- and (+)-(S)-citalopram, respectively, the serum t1/2 averaged 47 +/- 11 and 35 +/- 4 h and AUCss averaged 4,193 +/- 1,118 h.nmol/l and 2,562 +/- 1,190 h.nmol/l. The observed enantiospecificities were apparently more related to clearance, rather than to distributional mechanisms.