QUANTITATIVE STRUCTURE-METABOLISM RELATIONSHIPS FOR SUBSTITUTED BENZOIC-ACIDS IN THE RABBIT - PREDICTION OF URINARY-EXCRETION OF GLYCINE AND GLUCURONIDE CONJUGATES

1. Quantitative relationships between molecular physicochemical proper ties of 24 substituted benzoic acids and their metabolic fate in the r abbit have been investigated using computational chemistry and multiva riate statistical methods. 2. A total of 34 molecular properties were calculated for each compound using computational chemistry and were re lated statistically to the % molar recovery of glycine and glucuronide conjugates excreted in the urine of rabbits for the 24 compounds. 3. Compounds were successfully classified according to their dominant met abolic fate based on urinary excretion data, where stepwise linear reg ression analysis of the theoretical property data achieved good predic tive fits for observed versus predicted % molar urinary recovery as gl ucuronide conjugates (r(2) = 0.79) and % molar urinary recovery as gly cine conjugates (r(2) = 0.66). 4. Quantitative prediction of the urina ry excretion of glucuronide and glycine conjugates of the parent compo unds was achieved based on a statistical model using calculated molecu lar physicochemical parameters. Interpretation of the molecular proper ties, which are important for predicting the metabolic class, should g ive new insights into basic mechanisms of drug metabolism and underlyi ng molecular recognition events that determine disposition and metabol ism.