Genetic polymorphism of phenformin 4-hydroxylation

Area of Science:

• Pharmacogenetics
• Drug Metabolism
• Human Genetics

Background:

• Phenformin is an antidiabetic drug.
• Individual variability exists in phenformin's metabolic oxidation to 4-hydroxyphenformin.

Purpose of the Study:

• To investigate the genetic basis of phenformin hydroxylation variability.
• To determine if phenformin metabolism shares genetic control with other drugs.

Main Methods:

• Administered a single 50-mg dose of phenformin to 195 individuals.
• Measured urinary phenformin and 4-hydroxyphenformin ratios.
• Conducted family studies and compared with debrisoquine metabolic ratios.

Main Results:

• Urinary phenformin/4-hydroxyphenformin ratios varied widely (1-184).
• Variability consistent with autosomal recessive inheritance for impaired hydroxylation.
• High correlation (rs=0.785) between phenformin and debrisoquine metabolic ratios.

Conclusions:

• Phenformin hydroxylation exhibits genetic polymorphism, likely controlled by a single gene.
• Shared genetic control with debrisoquine metabolism is suggested.
• Implications for therapeutic response and potential toxicity in specific individuals.