TOLBUTAMIDE HYDROXYLATION IN HUMANS - LACK OF BIMODALITY IN 106 HEALTHY-SUBJECTS

The tolbutamide hydroxylation capacity was studied in 106 healthy unre lated volunteers from the Australian population. Following a 500 mg or al dose of tolbutamide, the ratio of metabolites (hydroxytolbutamide p lus carboxytolbutamide) to unchanged tolbutamide excreted in urine fro m 6 to 12 h post-dose (urinary metabolic ratio, MR) was determined. Me tabolic ratio values did not appear bimodally distributed, even follow ing various transformations of the data (i.e. Log10, inverse, Log10 in verse). A poor metabolizer (PM) subject from a previous clinical study , however, could be distinguished (MR value 159) from the above subjec ts (MR value range 324-303 3), particularly from the histogram plot of inverse tolbutamide metabolic ratio. The poor metabolizer's parents h ad metabolic ratio values (526 and 478) that were at the lower end of the range of metabolic ratios obtained from the population study, and may indicate that they both have a heterozygous genotype and that a re cessive form of inheritance is most likely. As the hydroxylations of t olbutamide and phenytoin are closely linked, the incidence of slow tol butamide metabolizers is likely to be similar to that for phenytoin (a bout 1: 500) and this is consistent with the failure to detect a singl e poor tolbutamide metabolizer in our random sample of 106 individuals .