Intra-individual variability and influence of urine collection period on dextromethorphan metabolic ratios in healthy subjects

The aim of the study was to evaluate intra-individual variability in metabo lic ratios (MRs) of dextromethorphan (DM) in healthy volunteers and to comp are the MRs in urine collected 0-4, 0-8 and 0-24 h post-dose. Urinary molar ratios of DM to dextrorphan (MR 1) and of DM to methoxymorphinan (MR2) wer e obtained after a single oral 27.5 mg dose of DM hydrobromide to ten healt hy male and four female Caucasians (ten extensive metabalizers (EM) and fou r poor metabolizers (PM) of DM) to probe activities of CYP2D6 and CYP3A. re spectively. Seven Ehl and one PM received DM on three additional occasions within 2 months. For the seven EM, the intraindividual variability (CVw) in the MRs obtained in the three urine collections ranged from 11 to 93% (MRI ) and from 8 to 77% (MR2). The mean CVw estimated separately for the 4, 8 a nd 24 h urines by two-way analysis of variance reached 58, 57 and 44% for t he MRI and 50. 42 and 31% for the MR2, respectively. For all 14 subjects, t he log-transformed ratios MR1) obtained in the 24 h urines were highly corr elated with those in either the 8 h (r, = 0.967, P < 0.0001) or 4 h urines (r(s) = 0.946, P < 0.0001). Correlation between the log transformed MR2s we re weaker (24 h vs. 8 h: r(s) = 0.829, P <0.0001, 24 h vs. 4 h: r(s) = 0.83 1; P < 0.0001). The MR1s in 4 h and 8 h urines were only 2 and 9% less than those in 24 h urines (median differences) and varied from 48 and 47% below to 85 and 55% above (95% -CI for the differences). However, the MR2s in th e 4 h and 8 h urines were shifted towards higher values by 49 and 23% and t he corresponding 95% -CI limits were: 16-164% (4 h vs. 24 h) and 30-119% (8 h vs. 24 h). In conclusion, MRI values in the 4 h urine collection agree w ell with those in longer collections and their use in epidemiological studi es can be recommended. The intra-individual variability of approximately 50 % in the MR1 has to be taken into account in clinical studies with within-s ubject design. Accurate determination of the MR2 requires at least a 24 h p eriod of urine collection.