Physiologically based pharmacokinetic model predictions of natural product-drug interactions between goldenseal, berberine, imatinib and bosutinib

Purpose 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. Methods PBPK models of hydrastine and berberine were de...

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Vydáno v:European journal of clinical pharmacology Ročník 78; číslo 4; s. 597 - 611
Hlavní autoři: Adiwidjaja, Jeffry, Boddy, Alan V., McLachlan, Andrew J.
Médium: Journal Article
Jazyk:angličtina
Vydáno: Berlin/Heidelberg Springer Berlin Heidelberg 01.04.2022
Springer Nature B.V
Témata:
Aniline Compounds
Antiretroviral drugs
Berberine
Biological Products
Biomedical and Life Sciences
Biomedicine
Cyclosporins
Cytochrome P-450 CYP3A - metabolism
Digoxin
Drug dosages
Drug interaction
Drug Interactions
Enzymes
Glycoproteins
Humans
Hydrastis - metabolism
Hydrastis canadensis
Imatinib
Imatinib Mesylate
Indinavir
Inhibitor drugs
Midazolam
Models, Biological
Natural products
Nitriles
P-Glycoprotein
Pharmacokinetics
Pharmacokinetics and Disposition
Pharmacology/Toxicology
Predictions
Quinolines
Berberine
Imatinib
Goldenseal
Physiologically based pharmacokinetic
Interactions
Bosutinib
ISSN:0031-6970, 1432-1041, 1432-1041
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Shrnutí:Purpose 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. Methods 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. Results 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 th to 95 th percentiles of prediction of 1.4–3.1) in systemic exposure (AUC) of bosutinib when co-administered with clinically relevant doses of goldenseal extract. A high dose of berberine (300 mg thrice daily) was also expected to affect bosutinib exposure, albeit to a lesser extent than that predicted with goldenseal (AUC ratio of 1.3, 5 th to 95 th percentile: 1.1–1.6). Conversely, the corresponding effects on imatinib exposure are unlikely to be of clinical importance (predicted AUC ratios of 1.0–1.2). Conclusion 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.
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ISSN:0031-6970
1432-1041
1432-1041
DOI:10.1007/s00228-021-03266-y