Defective hydroxylation of phenformin as a determinant of drug toxicity.
The kinetics of phenformin and its metabolite, p-hydroxyphenethylbiguanide, was studied in eight diabetic patients with varying degrees of renal impairment. Plasma and urinary phenformin and p-hydroxyphenethylbiguanide levels were determined by the multiple selected ion monitoring technique. Phenformin half-lives were unrelated to the degree of renal impairment, whereas reduced renal clearances of insulin and creatinine were significantly correlated with a prolonged half-life of the metabolite. The excretion of p-hydroxyphenethylbiguanide was quite variable (between 4.9% and 27% of total urinary drug loss), probably due to a genetic polymorphism of hepatic mechanisms for hydroxylation. A reduced formation of the metabolite was concomitant with marked increases in the amount of circulating phenformin. A positive reciprocal correlation was detected between areas under the plasma curve of phenformin and both the renal clearance of the unchanged drug and the percentage of metabolite formation. A reduced hydroxylation of phenformin seems, therefore, to be responsible for the high plasma levels of the drug previously described in toxic patients.
D000368:Aged; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010629:Phenformin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine*
C027283:4-hydroxyphenformin; D010629:Phenformin