Tolbutamide hydroxylation in humans: lack of bimodality in 106 healthy subjects.
The tolbutamide hydroxylation capacity was studied in 106 healthy unrelated volunteers from the Australian population. Following a 500 mg oral dose of tolbutamide, the ratio of metabolites (hydroxytolbutamide plus carboxytolbutamide) to unchanged tolbutamide excreted in urine from 6 to 12 h post-dose (urinary metabolic ratio, MR) was determined. Metabolic ratio values did not appear bimodally distributed, even following various transformations of the data (i.e. Log10, inverse, Log10 inverse). A poor metabolizer (PM) subject from a previous clinical study, however, could be distinguished (MR value 159) from the above subjects (MR value range 324-3033), particularly from the histogram plot of inverse tolbutamide metabolic ratio. The poor metabolizer's parents had 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 recessive form of inheritance is most likely. As the hydroxylations of tolbutamide and phenytoin are closely linked, the incidence of slow tolbutamide metabolizers is likely to be similar to that for phenytoin (about 1:500) and this is consistent with the failure to detect a single poor tolbutamide metabolizer in our random sample of 106 individuals.
Department of Clinical Pharmacology, Flinders University of South Australia, Bedford Park, Adelaide.
M E
ME
Veronese
J O
JO
Miners
D L
DL
Rees
D J
DJ
Birkett
D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D014044:Tolbutamide / Q000031:analogs & derivatives / Q000378:metabolism* / Q000652:urine; D000096926:Benzenesulfonamides
D014044:Tolbutamide; C006913:carboxytolbutamide; C031014:hydroxymethyltolbutamide; D000096926:Benzenesulfonamides