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

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Abstract
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 t½ 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. Chirality 9:686–692, 1997.