Recent trends in preclinical drug–drug interaction studies of flavonoids — Review of case studies, issues and perspectives

Abstract

Because of health benefits that are manifested across various disease areas, the consumption of herbal products and/or health supplements containing different kinds of flavonoids has been on the rise. While the drug-drug interaction potential between flavonoids and co-ingested drugs still remain an issue, opportunities exist for the combination of flavonoids with suitable anti-cancer drugs to enhance the bioavailability of anti-cancer drugs and thereby reduce the dose size of the anti-cancer drugs and improve its therapeutic index. In recent years, scores of flavonoids have undergone preclinical investigation with variety of drugs encompassing therapeutic areas such as oncology (etoposide, doxorubicin, paclitaxel, tamoxifen etc.), immunosuppression (cyclosporine) and hypertension (losartan, felodipine, nitrendipine etc.). The review provides examples of the recent trends in the preclinical investigation of 14 flavonoids (morin, quercetin, silibinin, kaempferol etc.) with various co-administered drugs. The relevance of combination of flavonoids with anti-cancer drugs and a framework to help design the in vitro and in vivo preclinical studies to gain better mechanistic insights are discussed. Also, concise discussions on the various physiological factors that contribute for the reduced bioavailability of flavonoids along with the significant challenges in the data interpretation are provided.

Dietary quercetin supplements: Assessment of online product informations and quantitation of quercetin in the products by high‐performance liquid chromatography

“…These include patients with impaired kidney function and with estrogen‐dependent cancer, because quercetin may aggravate kidney failure and may promote tumor formation in these patients, respectively (Andres et al, ). Quercetin and some of its metabolites may produce pharmacokinetic interactions with several drugs, primarily due to modulation of biotransformation enzymes and drug transporters (Miron et al, ; Srinivas, ). It has been reported that quercetin inhibits CYP enzymes (CYP3A4 and CYP2C9), sulfotransferases (SULT1), organic anion transporters (OAT1), organic anion‐transporting polypeptides (OATP1A2 and OATP2B1), and ATP‐binding cassette transporters (MRP1, P‐gp, and BCRP); while it increases the expression of CYP3A4, CYP1A1, and P‐gp (Kimura et al, ; Miron et al, ; Poór et al, ).…”

The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids

“…Because flavonoids and many prescribed medications share phase I and II metabolic processes, the effects of dietary flavonoid (and other bioactive) intake on drug ADME and dosing amounts have been of research and clinical interest for several decades (86–89). The impact of grapefruit consumption on cytochrome-3A4 activity and the metabolism of a large number of drug groups, such as calcium channel antagonists β-hydroxy-β-methylglutaryl–CoA reductase inhibitors and antihistamines, represents a widely cited example (90, 91).…”

Phenylephrine Pharmacokinetics and First-Pass Metabolism: What Is an Ideal Pharmacokinetic Surrogate?

“…For example, hesperidin has been shown to undergo extensive phase 2 conjugation, involving both glucuronosyltransferases and sulfotransferases in in vitro systems; similarly, biacalin and biochanin A demonstrate remarkable phase 2 metabolism. Overall, biliary mechanisms tend to be important for the disposition of flavonoids, as well as determining the drug-drug interaction potential with coadministered drugs [3,4].…”