Genetic polymorphism of phenformin 4-hydroxylation

Abstract

The ability to oxidize a single 50-mg dose of phenformin to its 4-hydroxy metabolite was determined in 195 individuals. Variations in the urinary ratio of phenformin/4-hydroxyphenformin ranged from 1-184. Family studies were consistent with the hypothesis that this variability resulted from a single gene mode of inheritance in which impaired hydroxylation of phenformin appears as an autosomal recessive trait. Both genotype frequencies and the degree of dominance of the extensive metabolizer phenotype over the recessive showed a remarkable resemblance to those described for debrisoquine 4-hydroxylation, which was confirmed by the high degree of correlation (rs = 0.785, P < 0.0001) between the phenformin ratio and the debrisoquine metabolic ratio. Such close agreement between the metabolism of these drugs may indicate that the same genetic control is in operation. Such genetic polymorphism of phenformin hydroxylation may have important implications for therapeutic response and for the possibility of toxic effects in a few individuals.