In vitro effect of Withania somnifera, AYUSH-64, and remdesivir on the activity of CYP-450 enzymes: Implications for possible herb−drug interactions in the management of COVID-19

Abstract

Ayurvedic medicines Withania somnifera Dunal (ashwagandha) and AYUSH-64 have been used for the prevention and management of COVID-19 in India. The present study explores the effect of Ashwagandha and AYUSH-64 on important human CYP enzymes (CYP3A4, CYP2C8, and CYP2D6) to assess their interaction with remdesivir, a drug used for COVID-19 management during the second wave. The study also implies possible herb−drug interactions as ashwagandha and AYUSH-64 are being used for managing various pathological conditions. Aqueous extracts of ashwagandha and AYUSH-64 were characterized using LC-MS/MS. A total of 11 and 24 phytoconstituents were identified putatively from ashwagandha and AYUSH-64 extracts, respectively. In addition, in silico studies revealed good ADME properties of most of the phytoconstituents of these herbal drugs and suggested that some of these might possess CYP-450 inhibitory activity. In vitro CYP-450 studies with human liver microsomes showed moderate inhibition of CYP3A4, 2C8, and 2D6 by remdesivir, while ashwagandha had no inhibitory effect alone or in combination with remdesivir. AYUSH-64 also exhibited a similar trend; however, a moderate inhibitory effect on CYP2C8 was noticed. Thus, ashwagandha seems to be safe to co-administer with the substrates of CYP3A4, CYP2C8, and CYP2D6. However, caution is warranted in prescribing AYUSH-64 along with CYP2C8 substrate drugs. Furthermore, preclinical and clinical PK studies would be helpful for their effective and safer use in the management of various ailments along with other drugs.

Pharmacological potential of Withania somnifera (L.) Dunal and Tinospora cordifolia (Willd.) Miers on the experimental models of COVID-19, T cell differentiation, and neutrophil functions

“…Withaferin A, which is another Withanolide derived from WS, has also been shown to possess anti-viral and immunomodulatory activity as per the in-silico studies ( 26 ). A detailed characterization of the active ingredients of WS along with other herbal extracts was reported recently by our group, in which the in-vitro anti-viral activity of WS extract components was shown for the first time ( 28 ). On the other hand, TC, another important herbal extract, has also been previously used and shown to have anti-viral potential through docking studies ( 25 ).…”

“…The filtrate obtained was assumed to be 100% aqueous extract which was further diluted in water to achieve a dosing concentration. The filtrate was further used for evaluating the composition and was previously published ( 28 ).…”

“…Other reports have shown Withaferin A, a bioactive steroidal lactone derived from WS, to be anti-inflammatory by reducing the levels of inflammatory cytokines such as IL-6 and TNFα which is desirable in COVID-19 patients to alleviate pulmonary pathology ( 26 , 27 ). More recently, we have also characterized the anti-viral component of WS which was found to exhibit potent anti-viral property in-vitro ( 28 ). Similarly, TC and PL have also been shown to modulate inflammatory responses in various disease conditions.…”

Phyto‐therapeutic potential of Withania somnifera: Molecular mechanism and health implications

“…There is a large body of information and scientific validation of activities reported for various plants parts of W. somnifera . Several activities including neuroprotection (Ahmad, Samuel, e al, 2016, Ahmad, Arya, et al, 2016), inflammatory (Chauhan et al, 2022), bone health (Khedgikar et al, 2013) anti‐cancer (Siddique et al, 2014; Sivasankarapillai et al, 2020; Yadav et al, 2022), antioxidant and, anti‐diabetic (Mikulska et al 2023) anti‐viral specially in Covid management (Kasarla et al, 2022) have been illustrated earlier wherein plant has shown promising effect (Fig. 1).…”

“…Withania somnifera Dunal (ashwagandha) and AYUSH‐64 were explored due to their possible action on human Cytochrome P450 enzymes to examine their interaction with remdesivir. The study has shown probable herb–drug interactions from AYUSH‐64 in managing different pathological conditions (Kasarla et al, 2022). Similarly, the phytochemicals of plants were studied in silico through docking for their inhibitory activity against various targets, including angiotensin‐converting enzyme 2 (ACE‐2), the SARS‐CoV‐2 receptor, and so on (Singh et al, 2022).…”