Influence of oxidation polymorphism on phenformin kinetics and dynamics

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Abstract
Plasma and urinary kinetics and responses of blood lactate, pyruvate and glucose after a single 50-mg phenformin dose were investigated in 8 subjects of known debrisoquinE oxidation phenotype, 4 poor metabolizers (PM) and 4 extensive metabolizers (EM). Higher peak plasma concentrations of phenformin (152.2 .+-. 12.7 ng/ml; mean .+-. SE) and a greater plasma AUC [area under the concentration-time curve] (799 .+-. 99 ng/h per ml) were reached in PM than in EM (99.8 .+-. 13.7 ng/ml and 549 .+-. 47 ng/h per ml). Although the urinary excretion of unchanged phenformin was greater in PM 2-24 h after dosing than in EM, excretion of 4-hydroxy-phenformin could not be detected in most samples collected from PM but was present in every sample from EM. Blood lactate concentrations increased dramatically in PM but fell in EM after phenformin. There were no changes in either blood pyruvate or glucose levels. The results may help to explain lactic acidosis in patients given phenformin in the absence of other predisposing factors.