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

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.

Pharmacokinetic Assessment of Rottlerin from Mallotus philippensis Using a Highly Sensitive Liquid Chromatography-Tandem Mass Spectrometry-Based Bioanalytical Method.

Rottlerin is a key bioactive phytoconstituent present in the pericarp of Mallotus philippensis. It shows promising multifaceted pharmacological actions against cancer. However, there is hardly any report for the quantification of rottlerin in the biological matrix and on its pharmacokinetic behavior. Therefore, we aimed in the present study to assess selective in vitro ADME properties and in vivo pharmacokinetics of isolated and characterized rottlerin using a newly developed and validated liquid chromatography-tandem mass spectrometry-based highly sensitive bioanalytical method. The method was found to be simple (mobile phase and analytical column), sensitive (1.9 ng/mL), and rapid (run time of 2.5 min). All the validation parameters were within the acceptable criteria of the United States Food and Drug Administration's bioanalytical method validation guideline. The method was found to be very useful to assess lipophilicity, plasma stability, metabolic stability, plasma protein binding of rottlerin, as well as its oral and intravenous pharmacokinetics in mice. Rottlerin showed a number of drug-like pharmacokinetic properties (in vitro). Moreover, it displayed an excellent half-life (>2 h) and oral bioavailability (>35%) as compared to other members of natural phenolics. The present study is the first-time report of in vitro ADME properties and in vivo preclinical pharmacokinetics of rottlerin. The generated information is very much useful for its further development as a phytotherapeutics toward cancer therapy.