Modulation of Major Human Liver Microsomal Cytochromes P450 by Component Alkaloids of Goldenseal: Time-Dependent Inhibition and Allosteric Effects.

Autor: McDonald MG; Departments of Medicinal Chemistry (M.G.M., A.E.R.) and Pharmaceutics (K.E.T.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences (D.-D.T., M.F.P.), College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington; and Center of Excellence for Natural Product Drug Interaction Research, Spokane, Washington (K.E.T., M.F.P., A.E.R.) Matthew.McDonald@Pfizer.com., Tian DD; Departments of Medicinal Chemistry (M.G.M., A.E.R.) and Pharmaceutics (K.E.T.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences (D.-D.T., M.F.P.), College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington; and Center of Excellence for Natural Product Drug Interaction Research, Spokane, Washington (K.E.T., M.F.P., A.E.R.)., Thummel KE; Departments of Medicinal Chemistry (M.G.M., A.E.R.) and Pharmaceutics (K.E.T.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences (D.-D.T., M.F.P.), College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington; and Center of Excellence for Natural Product Drug Interaction Research, Spokane, Washington (K.E.T., M.F.P., A.E.R.)., Paine MF; Departments of Medicinal Chemistry (M.G.M., A.E.R.) and Pharmaceutics (K.E.T.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences (D.-D.T., M.F.P.), College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington; and Center of Excellence for Natural Product Drug Interaction Research, Spokane, Washington (K.E.T., M.F.P., A.E.R.)., Rettie AE; Departments of Medicinal Chemistry (M.G.M., A.E.R.) and Pharmaceutics (K.E.T.), School of Pharmacy, University of Washington, Seattle, Washington; Department of Pharmaceutical Sciences (D.-D.T., M.F.P.), College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington; and Center of Excellence for Natural Product Drug Interaction Research, Spokane, Washington (K.E.T., M.F.P., A.E.R.).
Jazyk: angličtina
Zdroj: Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2020 Oct; Vol. 48 (10), pp. 1018-1027. Date of Electronic Publication: 2020 Jun 26.
DOI: 10.1124/dmd.120.091041
Abstrakt: Botanical and other natural products (NPs) are often coconsumed with prescription medications, presenting a risk for cytochrome P450 (P450)-mediated NP-drug interactions. The NP goldenseal ( Hydrastis canadensis ) has exhibited antimicrobial activities in vitro attributed to isoquinoline alkaloids contained in the plant, primarily berberine, (-)- β -hydrastine, and to a lesser extent, hydrastinine. These alkaloids contain methylenedioxyphenyl rings, structural alerts with potential to inactivate P450s through formation of metabolic intermediate complexes. Time-dependent inhibition experiments were conducted to evaluate their ability to inhibit major P450 activities in human liver microsomes by using a cocktail of isozyme-specific substrate probes. Berberine inhibited CYP2D6 (dextromethorphan O -demethylation; K I = 2.7 μM, k inact = 0.065 minute -1 ) and CYP3A4/5 (midazolam 1'-hydroxylation; K I = 14.8 μM, k inact = 0.019 minute -1 ); (-)- β -hydrastine inhibited CYP2C9 (diclofenac 4'-hydroxylation; K I = 49 μM, k inact = 0.036 minute -1 ), CYP2D6 ( K I > 250 μM, k inact > 0.06 minute -1 ), and CYP3A4/5 ( K I = 28 μM, k inact = 0.056 minute -1 ); and hydrastinine inhibited CYP2D6 ( K I = 37 μM, k inact = 0.049 minute -1 ) activity. Berberine additionally exhibited allosteric effects on midazolam hydroxylation, showing both positive and negative heterotropic cooperativity. Experiments with recombinant isozymes showed that berberine activated midazolam 1'-hydroxylation by CYP3A5, lowering K m(app) , but showed mixed inhibition and negative cooperativity toward this reaction when catalyzed by CYP3A4. Berberine inactivated CYP3A4 at a much faster rate than CYP3A5 and was a noncompetitive inhibitor of midazolam 4-hydroxylation by CYP3A4 but a strong mixed inhibitor of the CYP3A5 catalyzed reaction. These complex kinetics should be considered when extrapolating the risk for NP-drug interactions involving goldenseal. SIGNIFICANCE STATEMENT: Robust kinetic parameters were determined for the reversible and time-dependent inhibition of CYP2C9, CYP2D6, and CYP3A4/5 activities in human liver microsomes by major component isoquinoline alkaloids contained in the botanical natural product goldenseal. The alkaloid berberine also exhibited opposing, isozyme-specific allosteric effects on midazolam hydroxylation mediated by recombinant CYP3A4 (inhibition) and CYP3A5 (activation). These data will inform the development of a physiologically based pharmacokinetic model that can be used to predict potential clinically relevant goldenseal-drug interactions.
(Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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