curcumin and bosutinib

This study implements a physiologically based pharmacokinetic (PBPK) modelling approach to predict the effect of hydrastine and berberine, two major alkaloids present in goldenseal extract, on pharmacokinetics of imatinib and bosutinib.. PBPK models of hydrastine and berberine were developed in the Simcyp Simulator (version 17), integrating prior in vitro knowledge and published clinical pharmacokinetic data. The models account for reversible and irreversible (mechanism-based) inhibition of CYP3A enzymes as well as inhibition of the P-glycoprotein transporter. Inhibitory potencies of hydrastine and berberine on imatinib and bosutinib were estimated based on in vitro inhibition of metabolite formation.. The PBPK models provided reliable estimates on the magnitude of interactions due to co-administration of goldenseal extract or high-dose berberine on substrates of CYP3A enzymes (midazolam, indinavir and cyclosporine) and P-glycoprotein (digoxin). PBPK simulations predicted a moderate twofold increase (5. PBPK model-based predictions highlighted potential clinically significant interactions between goldenseal extract and bosutinib, but not imatinib. Dose adjustment may need to be considered if co-administration is desirable. These findings should be confirmed with optimally designed controlled drug interaction studies.

Topics: Aniline Compounds; Berberine; Biological Products; Cytochrome P-450 CYP3A; Drug Interactions; Humans; Hydrastis; Imatinib Mesylate; Models, Biological; Nitriles; Quinolines

This study aimed to investigate the potential pharmacokinetic interactions between curcumin, imatinib and bosutinib, combining In Vitro and in silico methods.. In Vitro metabolism of imatinib and bosutinib were investigated in pooled human liver microsomes and recombinant CYP3A4 enzyme in the presence and absence of curcumin and curcumin glucuronide using an LC-MS/MS assay for N-desmethyl metabolites. A physiologically-based pharmacokinetic (PBPK) model for curcumin formulated as solid lipid nanoparticles (SLN) was constructed using In Vitro glucuronidation kinetics and published clinical pharmacokinetic data. The potential effects of curcumin coadministration on systemic exposures of imatinib and bosutinib were predicted in silico using PBPK simulations.. Curcumin demonstrated potent reversible inhibition of cytochrome P450 (CYP)3A4-mediated N-demethylation of imatinib and bosutinib and CYP2C8-mediated metabolism of imatinib with inhibitory constants (k. A PBPK model for curcumin in a SLN formulation was successfully developed. Although curcumin possesses a strong In Vitro inhibitory activity towards CYP3A4 and CYP2C8 enzymes, its interactions with imatinib and bosutinib were unlikely to be of clinical importance due to curcumin's poor bioavailability.

Topics: Aniline Compounds; Chromatography, High Pressure Liquid; Curcumin; Cytochrome P-450 CYP2C8; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Glucuronides; Humans; Hydroxylation; Imatinib Mesylate; Microsomes, Liver; Models, Biological; Models, Molecular; Nitriles; Paclitaxel; Quinolines; Tandem Mass Spectrometry