Inhibition of the Conjugation of PABA with Glycine in Vitro by Sulfamoyl Benzoic Acids, Sulfonamides, and Penicillins and Its Relation to Tubular Secretion

Abstract

□ Elimination of drug molecules via tubular secretion is an important pharmacokinetic parameter especially for oral dosage forms where an extremely short half-life would prevent their application. We have studied the inhibition in vitro of the glycination of p-aminobenzoic acid (PABA) using rat liver microsomal preparations. The I50 values, the concentration of the inhibitor that leads to 50% inhibition of glycine conjugation of PABA as compared to the control, have been determined for sulfamoyl benzoic acids, sulfonamides, and penicillins. Statistically significant regression equations were derived explaining the observed variation in I50 values as a function of lipophilicity and steric bulk of the substituents for the combined set of sulfamoyl benzoic acids and sulfonamides (n=33). For the penicillins studied, only steric effects seem to be important for the explanation of the I50 values. Finally, regression analysis and the use of neural networks allowed the classification of compounds by their in vitro I50 values as being tubular secreted or not. Therefore, it can be concluded that the inhibition in vitro of the glycine conjugation of PABA is a useful model for the estimation of tubular secretion and drug interaction potential of acidic drug molecules in this process in vivo.