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A Systematic Approach to Evaluate Herb-Drug Interaction Mechanisms: Investigation of Milk Thistle Extracts and Eight Isolated Constituents as CYP3A4/5 Inhibitors.


Drug Metab Dispos. 2013 Jun 25;


Authors: Brantley SJ, Graf TN, Oberlies NH, Paine MF


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 CYP3A4/5 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 CYP3A4/5 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 semi-purified extract, silibinin, and the two associated constituents (silybin A, silybin B) demonstrated mechanism-based inhibition of recombinant CYP3A4 (KI ≈100 μM; kinact ≈0.20 min(-1)) but not microsomal CYP3A4/5 activity. The maximum predicted increase in midazolam AUC using the static mechanistic equation and recombinant CYP3A4 data was 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.

PMID: 23801821 [PubMed - as supplied by publisher]