Dextromethorphan to dextrorphan urinary metabolic ratio not sensitive enough to assess modest changes in CYP2D6 activity

The ability of the dextromethorphan (DTM) to dextrorphan (DT) urinary metabolic ratio (UMR) to detect subtle changes in CYP2D6 activity is not well defined. 10 extensive metabolizers and 1 poor metabolizer were studied on two separate occasions. Serum and urine were collected over 24 hours after DTM (30 mg) oral dosing. DTM and DT were quantitated by LC-MS (serum) and HPLC-fluorescence (urine). The DTM oral clearance (CLPO), DTM/DT AUC ratio, and DTM/DT UMR were determined. DTM CLPO was significantly correlated with the DTM/DT AUC ratio (r = 0.98) and DTM/DT UMR (n= 22; r = 0.765). Exclusion of the poor metabolizer resulted in loss of correlation between DTM CLPO and DTM/DT UMR (r <0.001) but not DTM/DT AUC ratio(r = 0.84). Intra and inter subject variability for DTM CLPO, DTM/DT AUC ratio, and DTM/DT UMR was estimated to be 15%, 26%, 35% and 32%, 68%, 100%, respectively. Assuming an effect size of 30%, type I error rate at 5%, 80% power and a crossover design requires a sample size of 14, 34 or 56 patients when the primary outcome measure is DTM CLPO, DTM/DT AUC ratio, DTM/DT UMR, respectively. If 14 subjects are used in a crossover study design and the DTM/DT UMR is used, the effect size would have to be 395% to maintain 80% power. Cross-sectional studies are similarly affected when the DTM/DT UMR is the principle outcome. The limitations of the DTM/DT UMR should be taken into account when modest effect sizes are expected. Supported by NIH Grants M01RR00750 and FDT001756. Clinical Pharmacology & Therapeutics (2004) 75, P82–P82; doi: 10.1016/j.clpt.2003.11.314