Abstract
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 N-β-d-glucuronidation, with Ki 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 IC50 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 O-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.
Highlights
Maytansine was first isolated in 1972 from the plant Maytenus ovatus [1] and showed potent cytotoxic effects in cell-based systems and efficacy in animal tumor models by binding to tubulin and blocking microtubule assembly [1,2,3,4,5]
The purpose of this study was to investigate the in vitro inhibitory potentials of mertansine on human uridine -diphospho-glucuronosyltransferase (UGT) activities including UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 in ultrapooled human liver microsomes and to evaluate the effect of mertansine on the mRNA levels of human CYP1A2, CYP2B6, CYP3A4, CYP2C8, CYP2C9, CYP2C19, UGT1A1, UGT1A4, and UGT1A9 in human hepatocytes to assess the potential for mertansine-induced drug interactions
These findings suggest the potential for drug–drug interactions (DDIs) between mertansine and UGT1A1, UGT1A3, or UGT1A4 substrates when used concomitantly
Summary
Maytansine was first isolated in 1972 from the plant Maytenus ovatus [1] and showed potent cytotoxic effects in cell-based systems and efficacy in animal tumor models by binding to tubulin and blocking microtubule assembly [1,2,3,4,5]. Maytansine failed as an anticancer drug in human clinical trials because of its unacceptable systemic toxicity [5,6,7]. Maytansinoids with potent cytotoxicity are clinically used and studied as the cytotoxic component of antibody–drug conjugates (ADCs) or aptamer-drug conjugates to reduce side effects and increase treatment effectiveness [7,8,9,10,11,12,13,14,15].
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