Plasma and urinary kinetics and responses of blood lactate, pyruvate, and glucose after a single 50-mg phenformin dose were investigated in eight subjects of known debrisoquin oxidation phenotype, four poor metabolizers (PM) and four extensive metabolizers (EM). Higher peak plasma concentrations of phenformin (152.2 +/- 12.7 ng/ml; mean +/- SE) and a greater plasma AUC (779 +/- 99 ng X hr X ml-1) were reached in PM than in EM (99.8 +/- 13.7 ng/ml and 549 +/- 47 ng X hr X ml-1). Although the urinary excretion of unchanged phenformin was greater in PM between 2 and 24 hr 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.