| Summary: | Mertansine, a tubulin inhibitor, is used as the cytotoxic component of antibody−drug conjugates (ADCs) for cancer therapy. The effects of mertansine on uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes and its effects on the mRNA expression of cytochrome P450s (CYPs) and UGTs in human hepatocytes were evaluated to assess the potential for drug−drug interactions (DDIs). Mertansine potently inhibited UGT1A1-catalyzed SN-38 glucuronidation, UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-β-glucuronidation, and UGT1A4-catalyzed trifluoperazine <i>N</i>-β-d-glucuronidation, with <i>K</i><sub>i</sub> values of 13.5 µM, 4.3 µM, and 21.2 µM, respectively, but no inhibition of UGT1A6, UGT1A9, and UGT2B7 enzyme activities was observed in human liver microsomes. A 48 h treatment of mertansine (1.25−2500 nM) in human hepatocytes resulted in the dose-dependent suppression of mRNA levels of CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, and UGT1A9, with IC<sub>50</sub> values of 93.7 109.1, 36.8 18.3, 160.6 167.4, 32.1 14.9, 578.4 452.0, 539.5 233.4, 856.7 781.9, and 54.1 29.1 nM, respectively, and decreased the activities of CYP1A2-mediated phenacetin <i>O</i>-deethylase, CYP2B6-mediated bupropion hydroxylase, and CYP3A4-mediated midazolam 1-hydroxylase. These in vitro DDI potentials of mertansine with CYP1A2, CYP2B6, CYP2C8/9/19, CYP3A4, UGT1A1, and UGT1A9 substrates suggest that it is necessary to carefully characterize the DDI potentials of ADC candidates with mertansine as a payload in the clinic.
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