Physiologically based pharmacokinetics of drug-drug interaction: A study of tolbutamide-sulfonamide interaction in rats

A blood flow rate-limited pharmacokinetic model was developed to study the effect of sulfonamide on the plasma elimination and tissue distribution of¹⁴C -tolbutamide (TB) in rats. The sulfonamides (SA) used were sulfaphenazole (SP), sulfadimethoxine (SDM), and sulfamethoxazole (SMZ). The tissue-to-plasma partition coefficients (Kp) of all tissues studied, i.e., lung, liver, heart, kidney, spleen, G.I. tract, pancreas, brain, muscle, adipose tissue, and skin, increased in the presence of SA, but except for brain, liver, and spleen, the tissue-to-plasma unbound concentration ratio (Kp, f) of other tissues did not show a significant alteration. This suggested that the tissue binding of TB is not affected by SA and that the increase of Kp is due mainly to the displacement of plasma protein-bound TB by SA. The concentrations of TB in several tissues and plasma were predicted by a physiologically based pharmacokinetic model using in vitro plasma binding and metabolic parameters, the plasma-to-blood concentration ratio and the tissue-to-plasma unbound concentration ratios having been determined from both the tissue and plasma concentrations of TB at the β-phase after intravenous administration of TB and the plasma free fraction. The predicted concentration curves of TB in each tissue and in plasma showed good agreement with the observed values except for the brain, for which the predicted concentrations were lower than the observed values in the early time period. In the SP- and SDM-treated rats, the predicted free concentration of TB in the target organ, the pancreas, at 6 h was six times higher than that of the control rats. From these findings, it is suggested that physiologically based pharmacokinetic analysis could be generally useful to predict approximate plasma and tissue concentrations of a drug in the presence of drug-drug interaction.