Physiologically-Based Pharmacokinetic Predictions of the Effect of Curcumin on Metabolism of Imatinib and Bosutinib: In Vitro and In Vivo Disconnect

Purpose This study aimed to investigate the potential pharmacokinetic interactions between curcumin, imatinib and bosutinib, combining In Vitro and in silico methods. Methods In Vitro metabolism of imatinib and bosutinib were investigated in pooled human liver microsomes and recombinant CYP3A4 enzym...

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Published in:Pharmaceutical research Vol. 37; no. 7; p. 128
Main Authors: Adiwidjaja, Jeffry, Boddy, Alan V, McLachlan, Andrew J
Format: Journal Article
Language:English
Published: New York Springer US 01.07.2020
Springer
Springer Nature B.V
Subjects:
Analysis
Aniline Compounds - metabolism
Bioavailability
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Bosutinib
Chromatography, High Pressure Liquid
Curcumin
Curcumin - analogs & derivatives
Curcumin - metabolism
Curcumin - pharmacokinetics
Cytochrome P-450 CYP2C8 - metabolism
Cytochrome P-450 CYP3A - metabolism
Cytochrome P-450 Enzyme Inhibitors - pharmacokinetics
Cytochrome P450
Demethylation
Drug Interactions
Enzymes
Glucuronides - metabolism
Humans
Hydroxylation
Imatinib
Imatinib Mesylate - metabolism
Inhibitor drugs
Liver
Medical Law
Metabolism
Metabolites
Microsomes
Microsomes, Liver - metabolism
Models, Biological
Models, Molecular
Nanoparticles
Nitriles - metabolism
Paclitaxel
Paclitaxel - metabolism
Pharmacokinetics
Pharmacology/Toxicology
Pharmacy
Quinolines - metabolism
Research Paper
Simulation methods
Tandem Mass Spectrometry
physiologically-based pharmacokinetic (PBPK)
imatinib
modelling and simulation
natural product-drug interactions
bosutinib
curcumin
ISSN:0724-8741, 1573-904X, 1573-904X
Online Access:Get full text
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Summary:Purpose This study aimed to investigate the potential pharmacokinetic interactions between curcumin, imatinib and bosutinib, combining In Vitro and in silico methods. 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. Results 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 i,u ) of ≤1.5 μmol. L −1 . A confirmatory In Vitro study with paclitaxel, the 6α-hydroxylation of which is exclusively mediated by CYP2C8, was consistent with a potent inhibition of this enzyme by curcumin. Curcumin glucuronide also inhibited both CYP enzymes In Vitro , albeit to a lesser extent than that of curcumin. PBPK model simulations predicted that at recommended dosing regimens of SLN curcumin , coadministration would result in an increase in systemic exposures of imatinib and bosutinib of up to only 10%. Conclusion 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.
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ISSN:0724-8741
1573-904X
1573-904X
DOI:10.1007/s11095-020-02834-8