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Enhancement of the 1‑Octanol/Water Partition Coefficient of the Anti-Inflammatory Indomethacin in the Presence of Lidocaine and Other Local Anesthetics

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...

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Bibliographic Details
Published in:The journal of physical chemistry. B 2015-07, Vol.119 (30), p.9868-9873
Main Authors: Tateuchi, Ryo, Sagawa, Naoki, Shimada, Yohsuke, Goto, Satoru
Format: Article
Language:English
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Summary: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 (ΔS 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 be increased by concurrent administration of the other drugs.
ISSN:1520-6106
1520-5207
DOI:10.1021/acs.jpcb.5b03984