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 inulin 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.
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Original Contributions|
August 01 1981
Defective Hydroxylation of Phenformin as a Determinant of Drug Toxicity
E Bosisio;
E Bosisio
Institute of Pharmacology and Pharmacognosy, School of Pharmacy, University of Milan
Milan, Italy
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M Galli Kienle;
M Galli Kienle
Institute of Chemistry, School of Medicine, University of Milan
Milan, Italy
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G Galli;
G Galli
Institute of Pharmacology and Pharmacognosy, School of Pharmacy, University of Milan
Milan, Italy
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C R Sirtori
C R Sirtori
Institute of Pharmacology and Pharmacognosy, School of Pharmacy, University of Milan
Milan, Italy
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Address reprint requests to Dr. Enrica Bosisio, Istituto di Farmacologia e Farmacognosia, Via Andrea del Sarto 21, 20129 Milano, Italia.
Diabetes 1981;30(8):644–649
Article history
Received:
December 04 1980
Revision Received:
March 18 1981
PubMed:
7250534
Citation
E Bosisio, M Galli Kienle, G Galli, M Ciconali, A Negri, A Sessa, S Morosati, C R Sirtori; Defective Hydroxylation of Phenformin as a Determinant of Drug Toxicity. Diabetes 1 August 1981; 30 (8): 644–649. https://doi.org/10.2337/diab.30.8.644
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