Physiologically-Based Pharmacokinetic Predictions of the Effect of Curcumin on Metabolism of Imatinib and Bosutinib: In
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RESEARCH PAPER
Physiologically-Based Pharmacokinetic Predictions of the Effect of Curcumin on Metabolism of Imatinib and Bosutinib: In Vitro and In Vivo Disconnect Jeffry Adiwidjaja 1 & Alan V Boddy 2,3 & Andrew J McLachlan 1
Received: 29 December 2019 / Accepted: 26 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT 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 (ki,u) of ≤1.5 μmol. L−1. A confirmatory In Vitro study with paclitaxel, the 6αhydroxylation of which is exclusively mediated by CYP2C8,
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11095-020-02834-8) contains supplementary material, which is available to authorized users. * Jeffry Adiwidjaja [email protected]
1
Sydney Pharmacy School, The University of Sydney, Sydney, NSW 2006, Australia
2
School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia
3
University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA 5000, Australia
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.
KEYWORDS bosutinib . curcumin . imatinib . modelling and simulation . natural product-drug interactions . physiologically-based pharmacokinetic (PBPK)
ABBREVIATIONS AUC CML CYP fuinc HIM HLM IVIVE ki M5 NDMI PBPK POR rCYP3A4 SLN SULT UGT
Area under the plasma concentration-time curve Chronic myeloid leukaemia Cytochrome P450 Unbound fracti
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