THE EXTENT AND DETERMINANTS OF CHANGES IN CYP2D6 AND CYP1A2 ACTIVITIES WITH THERAPEUTIC DOSES OF SERTRALINE

The extent of changes in CYP2D6 and CYP1A2 activities with higher ther apeutic dosages (>50 mg/day) of sertraline is not well established in vivo. This study assessed the extent and determinants of changes in CY P2D6 and CYP1A2 isozyme activities after treatment with clinically rel evant doses of sertraline. Patients and healthy volunteers aged 19 to 85 years (N = 21) were treated with sertraline for 5 to 55 days. The d osage of sertraline ranged from 25 to 150 mg/day (93.5 +/- 26.4 mg/day ; mean +/- SD). AU subjects had an extensive metabolizer phenotype for CYP2D6 and received a single oral dose of dextromethorphan (30 mg) an d caffeine (100 mg) before and after sertraline treatment. The log O-d emethylation ratio (ODMR) of dextromethorphan and the caffeine metabol ic ratio (CMR) in overnight urine were used as in vivo indices of the CYP2D6 and CYP1A2 isozyme activities, respectively. Concurrent medicat ions and Lifestyle habits (e.g., smoking and diet) were monitored duri ng the study. Baseline log ODMR (-2.33 +/- 0.45) but not CMR (5.1 +/- 1.9) (mean +/- SD) significantly changed after sertraline treatment (- 2.19 +/- 0.62; 4.5 +/- 1.6, respectively) (p: ODMR = 0.04, CMR = 0.10) . There was no significant effect of age, dose, duration of treatment, gender, sertraline and/or desmethylsertraline plasma concentration, s ubject type (patient or volunteer), and weight on the extent of change s in log ODMR or CMR (p > 0.05). In conclusion, sertraline treatment a t a mean daily dosage of 94.0 mg did not significantly change CYP1A2 a ctivity and resulted in a modest inhibition of CYP2D6 activity.