Effect of Myricetin on CYP2C8 Inhibition to Assess the Likelihood of Drug Interaction Using In Silico, In Vitro, and In Vivo Approaches

Abstract

Myricetin, a bioflavonoid, is widely used as functional food/complementary medicine and has promising multifaceted pharmacological actions against therapeutically validated anticancer targets. On the other hand, CYP2C8 is not only crucial for alteration in the pharmacokinetics of drugs to cause drug interaction but also unequivocally important for the metabolism of endogenous substances like the formation of epoxyeicosatrienoic acids (EETs), which are considered as signaling molecules against hallmarks of cancer. However, there is hardly any information known to date about the effect of myricetin on CYP2C8 inhibition and, subsequently, the CYP2C8-mediated drug interaction potential of myricetin at the preclinical/clinical level. We aimed here to explore the CYP2C8 inhibitory potential of myricetin using in silico , in vitro , and in vivo investigations. In the in vitro study, myricetin showed a substantial effect on CYP2C8 inhibition in human liver microsomes using CYP2C8-catalyzed amodiaquine- N -deethylation as an index reaction. Considering the Lineweaver–Burk plot, the Dixon plot, and the higher α-value, myricetin is found to be a mixed type of CYP2C8 inhibitor. Moreover, in vitro – in vivo extrapolation data suggest that myricetin is likely to cause drug interaction at the hepatic level. The molecular docking study depicted a strong interaction between myricetin and the active site of the human CYP2C8 enzyme. Moreover, myricetin caused considerable elevation in the oral exposure of amodiaquine as a CYP2C8 substrate via a slowdown of amodiaquine clearance in the rat model. Overall, the potent action of myricetin on CYP2C8 inhibition indicates that there is a need for further exploration to avoid drug interaction-mediated precipitation of obvious adverse effects as well as to optimize anticancer therapy.

Design, Synthesis, and Pharmacological Evaluation of Embelin–Aryl/alkyl Amine Hybrids as Orally Bioavailable Blood–Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer’s Disease: Discovery of SB-1448

“…CYP inhibition study of 9j was performed using USFDA-recommended CYP substrates, which are phenacetin (CYP1A2), bupropion (CYP2B6), amodiaquine (CYP2C8), diclofenac (CYP2C9), S -mephenytoin (CYP2C19), dextromethorphan (CYP2D6), and testosterone (CYP3A4) using earlier reported protocols. , The positive controls were fluvoxamine (0.0025–5 μM), ticlopidine (0.01–25 μM), quercetin (0.1–25 μM), sulfaphenazole (0.025–2.5 μM), tranylcypromine (0.1–50 μM), quinidine (0.01–10 μM), and ketoconazole (0.005–10 μM) for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. The reaction mixture consisted of phosphate buffer, MgCl 2 , substrate (CYP specific), positive control (CYP specific) or 9j , protein (HLM), and NADPH.…”

Cannabidiol-Based Prodrugs: Synthesis and Bioevaluation

“…We observed a variability in plasma concentration, which could be related to diverse reasons like degree of ionization through the pH range of gastrointestinal tract, intestinal reabsorption due to highly lipophilic nature, etc. The same effect had also been observed in the PK profile of drugs like etoposide, rifampicin, amodiaquine, etc. − Considering AUC data, 3a displayed 1.16-fold and 2.12–2.28-fold elevated plasma concentration of CBD 1 in comparison to its native form in mice and rat models, respectively. Likewise, 3aa showed 1.28–1.64-fold and 2.62–4.31-fold piping plasma concentration of CBD 1 in comparison to its native form in mice and rat models, respectively.…”

ADME/PK Insights of Crocetin: A Molecule Having an Unusual Chemical Structure with Druglike Features

“…CYP is a superfamily of enzymes that play a pivotal role in drug metabolism. Assessment of its potential to inhibit the CYP enzymes is critical as simultaneous administration with the drug of the same CYP substrate can affect the metabolic clearance of the drug. , This may cause augmentation of the plasma concentration of the drug, leading to the precipitation of potential dose-dependent adverse effects . Therefore, we determined the inhibitory action of crocetin for the USFDA-recommended panel of CYP isoforms using respective index reactions in HLM .…”