In healthy Caucasian subjects, the MRs of DM to DEX in plasma obtained at 3 h correlated reasonably well with those in urine collected over the time interval 0-4 h after the dose. Nevertheless, repeatability of this 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.

The aim of the study was to evaluate intra-individual variability in metabolic ratios (MRs) of dextromethorphan (DM) in healthy volunteers and to compare the MRs in urine collected 0-4, 0-8 and 0-24 h post-dose. Urinary molar ratios of DM to dextrorphan (MR1) and of DM to methoxymorphinan (MR2) were obtained after a single oral 27.5 mg dose of DM hydrobromide to ten healthy male and four female Caucasians (ten extensive metabolizers (EM) and four poor metabolizers (PM) of DM) to probe activities of CYP2D6 and CYP3A, respectively. Seven EM and one PM received DM on three additional occasions within 2 months. For the seven EM, the intra-individual variability (CVw) in the MRs obtained in the three urine collections ranged from 11 to 93% (MR1) and from 8 to 77% (MR2). The mean CVw estimated separately for the 4, 8 and 24 h urines by two-way analysis of variance reached 58, 57 and 44% for the MR1 and 50, 42 and 31% for the MR2, respectively. For all 14 subjects, the log-transformed ratios (MR1) obtained in the 24 h urines were highly correlated with those in either the 8 h (rs = 0.967, P < 0.0001) or 4 h urines (rs = 0.946, P < 0.0001). Correlation between the log-transformed MR2s were weaker (24 h vs. 8 h: rs = 0.829, P < 0.0001, 24 h vs. 4 h: rs = 0.831, 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 the 4 h and 8 h urines were shifted towards higher values by 49 and 23% and the corresponding 95% -CI limits were: 16-164% (4 h vs. 24 h) and 30-119% (8 h vs. 24 h). In conclusion, MR1 values in the 4 h urine collection agree well with those in longer collections and their use in epidemiological studies can be recommended. The intra-individual variability of approximately 50% in the MR1 has to be taken into account in clinical studies with within-subject design. Accurate determination of the MR2 requires at least a 24 h period of urine collection.

No abstract

The RP-HPLC capacity factors k of two series of 4-benzylthioderivatives, newly synthetised as potential antituberculous drugs, were determined on two types of C18 columns with methanol-water as the mobile phase, using UV detection. The measured log k values were compared with the log P values obtained by means of mathematical programmes and methods. High correlation was found between log P and log k values.