STEADY-STATE PHARMACOKINETICS OF THE ENANTIOMERS OF CITALOPRAM AND ITS METABOLITES IN HUMANS

The steady-state pharmacokinetics in serum and urine of the enantiomer s of citalopram and its metabolites, demethylcitalopram (DCT) and dide methylcitalopram (DDCT), were investigated after multiple doses of rac -citalopram for 21 consecutive days (40 mg per day) to healthy human s ubjects 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 fo r 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 m etabolites was observed. Serum levels of the (+)-(S)- enantiomers of c italopram, DCT, and DDCT throughout the steady-state dosing interval i nvestigated were 37 +/- 6%, 42 +/- 3% and 32 +/- 3%, respectively, of their total racemic serum concentrations. The (+)-(S)-enantiomers of c italopram, DCT, and DDCT were eliminated faster than their antipodes. For (-)-(R)- and (+)-(S)-citalopram, respectively, the serum t(1/2) av eraged 47 +/- 11 and 35 +/- 4 h and AUC(ss) averaged 4,193 +/- 1,118 h .nmol/l and 2,562 +/- 1,190 h.nmol/l. The observed enantiospecificitie s were apparently more related to clearance, rather than to distributi onal mechanisms. (C) 1997 Wiley-Liss, Inc.