Glucose oxidation to CO(2) in man at the fasted, steady state has been investigated in normal, hypothyroid, patients by monitoring the specific activity of plasma glucose and expired CO(2) after intravenous injection of glucose-1-(14)C, glucose-6-(14)C, and sodium bicarbonate-(24)C in tracer amounts. Making certain stoichiometric assumptions about the oxidation of the C-1 and C-6 carbons of glucose to CO(2), the data are incorporated into a multicompartmental model describing the kinetics of plasma glucose, plasma bicarbonate, and the conversion of glucose to CO(2) by the hexose monophosphate pathway and all other series and parallel pathways which oxidize glucose carbon to CO(2) (EMP-TCA). This formulation separates the distribution kinetics of glucose and bicarbonate from the kinetics of glucose oxidation to CO(2). It allows the calculation of a minimal fraction (varphi(t)) of glucose irreversibly oxidized to CO(2) which is based entirely on the duration of the experimental data. This calculation is independent of the extrapolative implications of the model beyond the experimental interval and of the particular model chosen to fit the data. All modeling and data fitting were performed on a digital computer with the SAAM program. Based on a 300 min experiment the analysis suggests that in hypothyroidism there is a decrease in the rate of glucose metabolized irreversibly (rhoG). There is also a decrease in the minimal fraction (varphi(300)) which is completely oxidized to CO(2) by way of the EMP-TCA. rhoG and varphi(300) are 0.56 and 0.42 mmole/min respectively as compared to 0.89 and 0.50 mmole/min respectively in normals. However, the fraction of the C-1 of glucose metabolized irreversibly which undergoes oxidation to CO(2) by the hexose monophosphate pathway (Psi) is not different from normal (0.07 and 0.07 respectively). The hyperthyroid studies suggest that rhoG and varphi(300) are within the normal range (1.01 and 0.46 mmoles/min respectively as compared to 0.89 and 0.50 mmole/min respectively in normals). However, Psi is decreased to less than half the normal value (0.03 as compared to 0.07 in normals).