Assessment of the Cytochrome P450 (CYP) interaction potential by Sideritis scardica hydroethanolic dry extract illuMind™

Sideritis scardica Griseb. (Lamiaceae), is a traditional medicinal plant for use in tea, tinctures or extracts. A good safety profile was reported recently [1]. Furthermore, the HMPC published the draft „Sideritis scardica Griseb., herba” for a list entry [2]. However, there was a lack of data concerning potential drug interaction.

The objective of the study was to characterize Extr. Sideritis scardica e herb. spir. sicc. (Ethanol 20% V/V; DER 6:1) with respect to the potential for CYP interaction in vitro. Therefore, the major human hepatic CYP isoenzymes were investigated according to the FDA and EMA guidance's [3, 4].

In a first part, putative cytotoxicity on primary human hepatocytes over the targeted concentration range for the test item (0.23 – 30 µg/ml) was examined. S. scardica extract did not display concentration-dependent reduction of relative viability and metabolic capacity of primary human hepatocytes during 72 hours of incubation. This enabled to use the highest tested concentration in the CYP induction assay. Therefore, the concentrations 30, 3, and 0.3 µg/ml were chosen to reach a broad concentration range. For the test item, no biologically relevant induction of functional enzyme activities occurred for CYP1A2, CYP2B6 and CYP3A4. Results obtained by qPCR confirmed the results observed in the functional activity test: neither CYP1A2, CYP2B6, nor CYP3A4 mRNA was increased in any of the donors.

In a second part the herbal test item was investigated for its potential to inhibit the human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isoenzymes in pooled human liver microsomes. Finally, S. scardica extract demonstrated only a weak to mild inhibition against the in vitro activity of the investigated CYP enzymes, which is far away from clinically relevant plasma concentrations.

These data in combination with the lack of induction potential demonstrates that clinically relevant drug interactions caused by Sideritis scardica dry extract are unlikely.

References:

[1] Feistel B et al. Toxins 2018; 10: 258. doi:10.3390/toxins10070258

[2] EMA/HMPC. European Union list entry (draft) on Sideritis scardica Griseb., herba. 2015. http://www.ema.europa.eu/docs/en_GB/document_library/Herbal List entry/2015/07/WC500190614.pdf

[3] FDA Draft Guidance for Industry: In vitro Metabolism and Transporter-Mediated Drug-Drug Interaction Studies (October 2017)

[4] European Medicines Agency. Guideline on the Investigation of Drug Interactions, CPMP/EWP/560/95/Rev. 1 (June 2012)