Triclosan is a pan-uridine 5'-diphospho-glucuronosyltransferase (UGT) and pan-cytochrome P450 (CYP) inhibitor with high selectivity towards CYP2C19

Understanding the clearance pathways of drug candidates and the fraction metabolized (f _m ) by drug-metabolizing enzymes is one of the major focuses 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. Kinetic analysis revealed noncompetitive inhibition of UGT1A3-mediated telmisartan glucuronidation by triclosan, where the other tested compounds failed to inhibit UGT1A3. However, triclosan also inhibited multiple CYP enzymes with IC₅₀ values ranging from 0.12-22 µM, limiting its utility as a tool compound to evaluate f _m by UGT. Notably, triclosan demonstrated high selectivity and potency toward CYP2C19 (IC ₅₀ 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.