An In Vitro Evaluation of the Inhibition of Recombinant Human Carboxylesterase-1 by Herbal Extracts

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Hajra Mazhar
Philippe Robaey
Cory Harris


natural health products, herb-drug interactions, pharmacokinetics, drug metabolizing enzymes, integrative medicine, dietary supplements, adverse events, polypharmacy


Introduction: Methylphenidate is a psychostimulant prescribed for symptoms of attention-deficit hyperactivity disorder (ADHD), and is metabolized by carboxylesterase-1 (CES1) enzyme. There is little information on herbal medicine used for ADHD and their interactions with CES1.

Methods: An in vitro study was conducted with extracts of 21 herbal medicines using a recombinant human CES1 enzyme inhibition assay to determine if the extracts influence enzyme activity. Extracts were initially evaluated for their potential to inhibit CES1 metabolism of 4-nitrophenyl acetate using an in vitro Microtiter plate enzyme inhibition assay. The most active extracts were serially diluted to establish the half maximal inhibitory concentration (IC50) and were then tested for potential irreversible inhibition using a time-dependence enzyme assay. Phytochemical characterization of selected extracts was performed, and marker compounds were evaluated for their potential to inhibit CES1-mediated metabolism of the probe substrate.

Results: The extracts exhibited a range of inhibition of CES1 activity, ranging from 15–95% at a standard screening concentration of 200 ?g/mL. Rhodiola rosea was the most potent inhibitor of CES1 (IC50 = 4.7 ?g/mL). No time-dependent inhibitors of CES1 were identified in this study. At 10 ?g/mL, marker compounds of ginger, [8]-gingerol (60.3%) and [10]-gingerol (67.2%), showed significant (P < 0.05) inhibition of CES1 compared to vehicle control.

Discussion: The herbal medicine extracts showed varying inhibition at supraphysiologic concentrations and no risk of mechanism-based inhibition was observed. Herbal medicine used by ADHD patients have the potential to interact with CES1-mediated metabolism. To mitigate potential risk of herb-drug interactions, patients using herbal medicine alongside CES1-metabolized drugs should discuss their use with healthcare professionals.

Conclusions: In vivo and clinical research are required to determine if the potential interactions would significantly affect safety and efficacy of methylphenidate at a clinical level.

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