Complementary products and drug interactions: screening for the potential to cause pharmacokinetic interactions
Creators: name: Sevior, Danielle
Publisher: name: RMIT University
Year: 2024

description: The use of complementary products has increased dramatically over the last few decades. These products are not subjected to the same safety and toxicity testing that we demand of our conventional medicines, yet they are consumed without medical supervision or advice. The concurrent use of these products with conventional medicines raises the potential for drug interactions to occur. We investigated the potential for complementary products to interact with three key pharmacokinetic parameters. The displacement of drugs bound to plasma proteins; inhibition of the transporter p-glycoprotein; and inhibition of the quantitative most important class of drug metabolising enzymes, the cytochrome P450s.<br><br>Complementary products selected for investigation are likely to be concurrently used with a therapeutic drug for which, if an interaction was to occur, the outcome could be life threatening. This is based on the properties of the drug and the reported traditional therapeutic indication. <br><br>Site-specific fluorescent probes were employed for albumin and alpha-1-acid glycoprotein to determine the binding and displacement of previously bound compounds. Of the 5 products investigated significant binding (K<sub>d</sub> &lt; 1mg/ml) occurred at site I on human serum albumin for 1 extract (the methanolic extract of Goldenseal). A greater level of significant binding was seen at site II with 1 aqueous extract (CoEnzyme Q10) and 4 methanolic extracts (CoEnzyme Q10, Danshen, Ginkgo Biloba, Goldenseal) all binding with a dissociation constant less than 1 mg/ml. Investigations into binding to alpha-1-acid glycoprotein revealed that 1 product bund with significance (the methanolic extract of Echinacea).<br><br>Inhibition of the transcellular membrane pump p-glycoprotein was investigated with 5 products utilizing a rapid fluorescent assay and the data confirmed with the enzyme based ATPase assay. Significant inhibition (IC<sub>50</sub> &lt;100 μg/ml) was seen for 4 extracts (the aqueous extract of Cordyceps, the methanolic extract of Milk Thistle and both aqueous and methanolic extracts for Slippery Elm).<br><br>The inhibition of cytochrome P450 was determined for 9 isoforms of the enzyme. Two methods were used; HPLC analysis combined with fluorometry with single substrates and their metabolites, and the N-in-one cocktail, which allows for the simultaneous monitoring of the 9 enzymes in a single incubation. The N-in-one assay was a more reliable assay with these complex products. Of the ten investigated products, Valerian was the most widely inhibitory as it inhibited all 9 of the isoenzymes to some degree. The inhibition of CYP3A4 by the methanolic extract was the most significant finding (IC<sub>50</sub> 3.5µg/ml). Reliable extrapolation of in vitro findings to in vivo situation is still an unsurmountable challenge.<br><br>Due to the large number of complementary products available, their variability in chemical composition and the requirement of ongoing monitoring, we have utilised assays that can provide rapid, cost-effective and reliable information with regards to the potential of these products to cause drug interaction. We have demonstrated the ability for rapid, accurate and reproducible assays to provide information on the potential for complementary products to cause drug interactions and presented a rationale basis for screening these products.