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

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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 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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Abbreviations

AUC:

Area under the plasma concentration-time curve

CML:

Chronic myeloid leukaemia

CYP:

Cytochrome P450

fuinc :

Unbound fraction during incubation

HIM:

Human intestinal microsomes

HLM:

Human liver microsomes

IVIVE:

In Vitro to In Vivo extrapolation

ki :

Inhibitory constant

M5:

N-desmethyl bosutinib

NDMI:

N-desmethyl imatinib

PBPK:

Physiologically-based pharmacokinetic

POR:

P450 reductase

rCYP3A4:

Recombinant human CYP3A4 enzyme

SLN:

Solid lipid nanoparticles

SULT:

Sulphotransferase

UGT:

Uridine 5′-diphospho-glucuronosyltransferase

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Acknowledgments and Disclosures

The In Vitro study was supported by a research grant from Indonesia Endowment Fund for Education (LPDP), Ministry of Finance of the Republic of Indonesia. J.A. is receiving a postgraduate scholarship from Indonesia Endowment Fund for Education (LPDP). Certara UK Limited (Simcyp Division) is gratefully acknowledged for providing the access to the Simcyp Simulator. There are no competing interests to declare.

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Authors and Affiliations

  1. Sydney Pharmacy School, The University of Sydney, Sydney, NSW, 2006, Australia

    Jeffry Adiwidjaja & Andrew J McLachlan

  2. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, 5001, Australia

    Alan V Boddy

  3. University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, 5000, Australia

    Alan V Boddy

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  1. Jeffry Adiwidjaja
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  2. Alan V Boddy
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Contributions

J.A., A.V.B. and A.J.M. designed the research and contributed to the interpretation. J.A. performed the simulations and In Vitro experiments, analysed the data and drafted the manuscript. A.V.B. and A.J.M. critically revised the manuscript.

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Correspondence to Jeffry Adiwidjaja.

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Adiwidjaja, J., Boddy, A.V. & McLachlan, A.J. Physiologically-Based Pharmacokinetic Predictions of the Effect of Curcumin on Metabolism of Imatinib and Bosutinib: In Vitro and In Vivo Disconnect. Pharm Res 37, 128 (2020). https://doi.org/10.1007/s11095-020-02834-8

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