Side effects and excessive potentiation of drug efficacy caused by polypharmacy are becoming important social issues. The apparent partition coefficient of indomethacin (log P'(IND)) increases-in the presence of lidocaine, and this is used as a physicochemical model for investigating polypharmacy, We examined the changes in log P'(IND) caused by clinically used local anesthetics-lidocaine, tetracaine, mepivacaine, bupivacaine, and dibucaine-and by structurally similar basic drugs-procainamide, imipramine, and diltiazem. The quantitative structure-activity relationship study of log P'(IND) showed that the partition coefficient values (log P-LA) and the structural entropic terms (Delta S-obs, log f) of the additives affect log P'(IND). These results indicate that the local, anesthetics and structurally similar drugs function as phase-transfer catalysts, increasing the membrane permeability of indomethacin via heterogeneous intermolecular association. Therefore we expect that the potency of indomethacin, an acidic nonsteroidal anti-inflammatory drug, will he increased by concurrent administration of the other drugs.