In-vivo indices of CYP2D6 activity: comparison of dextromethorphan metabolic ratios in 4-h urine and 3-h plasma

Objectives: Dextromethorpan (DM) is widely used as a probe drug to assess i n vivo the activity of the cytochrome P450 2D6 (CYP2D6). The aim of the stu dy was to compare metabolic ratios (MRs) of DM to dextrorphan (DEX) in plas ma and urine. We examined, separately in urine and plasma, the relationship s between the MRs which are based on DEX and those involving the sum of DEX and a secondary metabolite hydroxymorphinan (HM). Furthermore, we compared the MRs in plasma obtained with and without hydrolysis of DEX glucuronides . Methods: Concentrations of DM and metabolites in urine and plasma were dete rmined by HPLC after a single oral dose of 30 mg DM hydrobromide to 101 hea lthy Caucasian subjects. Urine was collected over the time interval 0-4 h a fter the dose and plasma was obtained from 95 subjects 3 h after administra tion. Results. Six subjects (5.9%) were of poor metaboliser (PM) phenotype (urinary DM:DEX ratio >0.3). A good correlation (r(2) = 0.777, P < 0.00001) was observed between the metabolic ratios of DM:DEX in plasma and urine. T here was an excellent correlation, both in plasma and urine, between the lo g-transformed ratios of DM:DEX and of DM to the sum of molar concentrations of DEX and HM (r(2) > 0.996, P < 0.00001). Plasma samples of 89 subjects ( 83 EM and 6 PM) were analyzed without deconjugation of DEX glucuronide also . The correlation between the plasma ratios of DM:DEX glucuronide (r(2) = 0 .793, P < 0.00001) was comparable to that reported by other authors on urin e. Conclusion. In healthy Caucasian subjects, the MRs of DM to DEX in plasma o btained at 3 h correlated reasonably well with those in urine collected ove r the time interval 0-4 h after the dose. Nevertheless, repeatability of th is plasma index should be determined before its wide use can be recommended . Finally, the interindividual variation in DEX metabolism to HM (catalyzed by CYP3A) contributes only minimally to the interindividual variability of the MRs.