Polymorphic drug oxidation: pharmacokinetic basis and comparison of experimental indices.

Abstract

1 The pharmacokinetic basis for using various experimental indices, (urinary drug: metabolite and metabolite:drug + metabolite ratios, urinary metabolite recovery and AUC values), for detecting polymorphic oxidative drug metabolism was examined. Pharmacokinetic determinants in addition to partial metabolic clearance down the polymorphic route were identified in each index. 2 The ability of the various indices to discriminate bimodality in population data was assessed using a computer simulation. 3 With the exception of the AUC data, bimodality was apparent to varying extents in all of the frequency distributions and, in general, logarithmic transformation allowed clearer visualisation of the two phenotypic groups. 4 Simulated distributions were compared with those observed experimentally for metoprolol and its ox-hydroxy metabolite. 5 Detailed pharmacokinetic data from controlled studies in small numbers of volunteers can form the basis of the input to the simulation programme. Inspection of the output may help in the design of further studies in larger numbers of subjects in whom only limited data collection is possible.

Testing for bimodality in frequency distributions of data suggesting polymorphisms of drug metabolism‐histograms and probit plots.

“…For example, the distribution of the area under the plasma drug concentration-time curve is usually positively skewed because this index is related inversely to the clearance of the drug. Similarly, the distribution of the urinary drug/metabolite ratio can be skewed dependent upon the means and variances of the renal and non-renal clearances of the parent drug (Jackson et al, 1986 puter simulation to explore the ability of these graphical methods to detect bimodality in frequency distributions.…”

Relationship between plasma oxipurinol concentrations and xanthine oxidase activity in volunteers dosed with allopurinol.

“…1-MU is the only metabolic product of 1-MX and this reaction is catalysed by xanthine oxidase (Birkett et al, 1983). The use of the ratio of product to substrate in urine collections, as an indication of the metabolic clearance of substrate, has been described previously (Jackson et al, 1986;Birkett et al, 1987). A further assumption, made when using this approach, was that allopurinol does not affect the renal clearance of 1-MU or 1-MX.…”

Determination of debrisoquine metabolic ratio from hourly urine collections in healthy volunteers.

“…Peart et al (1986) have demonstrated an excellent correlation between DMR obtained by 4 h and 8 h urine collection. Jackson et al (1986) explored the pharmacokinetic basis of the urinary drug/metabolite ratio in a model drug with kinetic properties similar to that of D. They concluded that the time of urine collection would make little difference to the frequency distribution of the metabolic ratio. Table 1 shows that hourly sampling of urine was unable to provide adequate data for the calculation of the DMR in PM subjects.…”

“…With the small number of subjects studied it is not possible to infer from the present work whether phenotyping by a short urine collection, as suggested above, will result in a shift of the antimode. Jackson et al (1986) suggested that a change in the antimode would occur only when urine collection time was a small fraction of the elimination half-life of the parent drug. P.A.P.…”