Submission Title

Determining the Fraction Unbound of Herbal Product Constituents in Human Liver Microsomes to Improve Herb-Drug Interaction Predictions

Session Number

PS1

Location

Graves Gym

Abstract Number

PS1-t

Abstract

Inhibition of drug metabolizing enzymes by herbal constituents is a common mechanism underlying adverse herb-drug interactions. Inhibition constants (Kis) for isolated constituents of the herbal product, milk thistle, towards multiple drug metabolizing enzymes were previously assessed. The fraction unbound (fu) for each constituent was determined in this work to calculate ‘true’ Ki to improve interaction prediction accuracy. Mixtures containing human liver microsomes and milk thistle constituent or binding control were added to the donor side of semipermeable membranes in an equilibrium dialysis device; buffer was added to the receiver. At equilibrium, aliquots were collected and analyzed by LC-MS/MS. fu was calculated by dividing the peak area ratio (analyte/internal standard) of the receiver to that of the donor side. High and low binding control fu was 0.60±0.09 and 1.02±0.17, respectively. Constituent fu was high (0.99±0.07 to 1.21±0.09), indicating negligible impact on true Ki.

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Apr 23rd, 10:45 AM Apr 23rd, 12:15 PM

Determining the Fraction Unbound of Herbal Product Constituents in Human Liver Microsomes to Improve Herb-Drug Interaction Predictions

Graves Gym

Inhibition of drug metabolizing enzymes by herbal constituents is a common mechanism underlying adverse herb-drug interactions. Inhibition constants (Kis) for isolated constituents of the herbal product, milk thistle, towards multiple drug metabolizing enzymes were previously assessed. The fraction unbound (fu) for each constituent was determined in this work to calculate ‘true’ Ki to improve interaction prediction accuracy. Mixtures containing human liver microsomes and milk thistle constituent or binding control were added to the donor side of semipermeable membranes in an equilibrium dialysis device; buffer was added to the receiver. At equilibrium, aliquots were collected and analyzed by LC-MS/MS. fu was calculated by dividing the peak area ratio (analyte/internal standard) of the receiver to that of the donor side. High and low binding control fu was 0.60±0.09 and 1.02±0.17, respectively. Constituent fu was high (0.99±0.07 to 1.21±0.09), indicating negligible impact on true Ki.