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Phytother Res ; 36(10): 3988-4001, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35778986

RESUMEN

Dietary polyphenols such as quercetin and curcumin have been extensively administered to patients with cancer in the form of herbal supplements. They may have a synergistic anticancer effect; however, a risk of pharmacokinetic interactions with selective CDK-4/6 inhibitors that are metabolized by the CYP3A4 enzyme exists. Considering these pharmacokinetic aspects, the current study examined the effects of curcumin and quercetin on human CYP3A4 to ascertain CYP3A4-mediated herb-drug interactions with CDK inhibitors. In this study, using in silico methods and CYP3A4 inhibition kinetics in human liver microsomes and recombinant CYP3A4 enzymes, the effects of concentration-dependent inhibition of CYP3A4 by quercetin and curcumin on CDK inhibitors metabolism were examined. Based on our in-silico docking findings, curcumin and quercetin were considerably bound to CYP3A4 protein and displace CDK inhibitors from the CYP3A4 substrate binding domain. The IC50 values of curcumin and quercetin were 16.10 and 0.05 µM, respectively, for CYP3A4-mediated 1'-hydroxylation of midazolam. The dietary polyphenols prolonged the in vitro half-life of palbociclib and ribociclib by 6.4-fold and decreased their intrinsic microsomal clearance by approximately 4.6 times. Our findings indicate that curcumin and quercetin effectively cause herb-drug interactions and should be cautiously used to avoid therapeutic failure.


Asunto(s)
Neoplasias de la Mama , Curcumina , Inhibidores del Citocromo P-450 CYP3A , Interacciones de Hierba-Droga , Neoplasias de la Mama/metabolismo , Curcumina/farmacología , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacología , Femenino , Humanos , Microsomas Hepáticos , Midazolam/farmacología , Simulación de Dinámica Molecular , Polifenoles/farmacología , Quercetina/farmacología
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