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<p>Understanding the clearance pathways of drug candidates and the fraction metabolized (f<sub>m</sub>) by drug-metabolizing enzymes is a major focus during drug discovery and development process. While selective cytochrome P450 (CYP) inhibitors are widely available, the lack of potent pan- uridine 5’-diphospho-glucuronosyltransferases (UGT) inhibitors with minimal cross-inhibition on CYP enzymes limits the ability to evaluate the contribution of UGT to drug clearance in vitro and in vivo. This study screened five potential inhibitors—triclosan, salicylamide, valproic acid, benzoic acid, and borneol—across twelve human UGT isoforms using human liver microsomes (HLM) and Supersome®. Triclosan emerged as a potent pan-UGT inhibitor, exhibiting IC<sub>50</sub> values below 10 µM for all tested isoforms, ranging from 0.43–9.9 µM. However, triclosan also inhibited multiple CYP enzymes with IC<sub>50</sub> values ranging from 0.12 to 22 µM. The concurrent inhibition of multiple CYP enzymes limits the application of triclosan as a selective tool compound for UGT reaction phenotyping. The kinetic analysis revealed noncompetitive inhibition of UGT1A3-mediated telmisartan glucuronidation by triclosan, where the other tested compounds failed to inhibit UGT1A3. Notably, triclosan demonstrated high selectivity and potency toward CYP2C19 (IC<sub>50</sub> 0.12 µM), suggesting its potential use in CYP2C19 reaction phenotyping in HLM. Additionally, triclosan selectively inhibited flavin-containing monooxygenase 3 (FMO3) but not FMO5.</p><p></p>

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Triclosan concurrently inhibits UGT and CYP enzymes but shows high selectivity toward CYP2C19

  • 期刊论文

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  • 发表日期：

    2025年10月29日

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  • Guo Zhong,
  • Megha Chandrashekhar,
  • Theresa Aliwarga

摘要

Understanding the clearance pathways of drug candidates and the fraction metabolized (fm) by drug-metabolizing enzymes is a major focus during drug discovery and development process. While selective cytochrome P450 (CYP) inhibitors are widely available, the lack of potent pan- uridine 5’-diphospho-glucuronosyltransferases (UGT) inhibitors with minimal cross-inhibition on CYP enzymes limits the ability to evaluate the contribution of UGT to drug clearance in vitro and in vivo. This study screened five potential inhibitors—triclosan, salicylamide, valproic acid, benzoic acid, and borneol—across twelve human UGT isoforms using human liver microsomes (HLM) and Supersome®. Triclosan emerged as a potent pan-UGT inhibitor, exhibiting IC50 values below 10 µM for all tested isoforms, ranging from 0.43–9.9 µM. However, triclosan also inhibited multiple CYP enzymes with IC50 values ranging from 0.12 to 22 µM. The concurrent inhibition of multiple CYP enzymes limits the application of triclosan as a selective tool compound for UGT reaction phenotyping. The kinetic analysis revealed noncompetitive inhibition of UGT1A3-mediated telmisartan glucuronidation by triclosan, where the other tested compounds failed to inhibit UGT1A3. Notably, triclosan demonstrated high selectivity and potency toward CYP2C19 (IC50 0.12 µM), suggesting its potential use in CYP2C19 reaction phenotyping in HLM. Additionally, triclosan selectively inhibited flavin-containing monooxygenase 3 (FMO3) but not FMO5.