Journal article
A systematic approach to evaluate herb-drug interaction mechanisms: investigation of milk thistle extracts and eight isolated constituents as CYP3A inhibitors
Drug metabolism and disposition, Vol.41(9), pp.1662-1670
09/2013
Handle:
https://hdl.handle.net/2376/114049
PMCID: PMC3876807
PMID: 23801821
Abstract
Despite increasing recognition of potential untoward interactions between herbal products and conventional medications, a standard system for prospective assessment of these interactions remains elusive. This information gap was addressed by evaluating the drug interaction liability of the model herbal product milk thistle (Silybum marianum) with the CYP3A probe substrate midazolam. The inhibitory effects of commercially available milk thistle extracts and isolated constituents on midazolam 1'-hydroxylation were screened using human liver and intestinal microsomes. Relative to vehicle, the extract silymarin and constituents silybin A, isosilybin A, isosilybin B, and silychristin at 100 μM demonstrated >50% inhibition of CYP3A activity with at least one microsomal preparation, prompting IC50 determination. The IC50s for isosilybin B and silychristin were ∼60 and 90 μM, respectively, whereas those for the remaining constituents were >100 μM. Extracts and constituents that contained the 1,4-dioxane moiety demonstrated a >1.5-fold shift in IC50 when tested as potential mechanism-based inhibitors. The semipurified extract, silibinin, and the two associated constituents (silybin A and silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (KI, ∼100 μM; kinact, ∼0.20 min(-1)) but not microsomal CYP3A activity. The maximum predicted increases in midazolam area under the curve using the static mechanistic equation and recombinant CYP3A4 data were 1.75-fold, which may necessitate clinical assessment. Evaluation of the interaction liability of single herbal product constituents, in addition to commercially available extracts, will enable elucidation of mechanisms underlying potential clinically significant herb-drug interactions. Application of this framework to other herbal products would permit predictions of herb-drug interactions and assist in prioritizing clinical evaluation.
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Details
- Title
- A systematic approach to evaluate herb-drug interaction mechanisms: investigation of milk thistle extracts and eight isolated constituents as CYP3A inhibitors
- Creators
- Scott J Brantley - Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USATyler N GrafNicholas H OberliesMary F Paine
- Publication Details
- Drug metabolism and disposition, Vol.41(9), pp.1662-1670
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- United States
- Grant note
- R01-GM077482 / NIGMS NIH HHS UL1TR000083 / NCATS NIH HHS R01 GM077482 / NIGMS NIH HHS UL1 TR000083 / NCATS NIH HHS
- Identifiers
- 99900547796901842
- Language
- English
- Resource Type
- Journal article