Evaluation of the effect of quercetin treatment on CYP2C9 enzyme activity of diclofenac in healthy human volunteers

Abstract

The purpose of present study was to evaluate the effect of quercetin on pharmacokinetics of diclofenac sodium (DIC) in healthy volunteers. The open-label, 2 period, sequential study was conducted in 12 healthy volunteers. DIC 100 mg was administered during control and after quercetin phases. Quercetin 500 mg was administered twice daily for 10 days during quercetin phase. Treatment with quercetin significantly enhanced maximum plasma concentration (C ) area under the curve (AUC ), and half life, while significantly decreased elimination rate constant (k ) and apparent oral clearance (CL/F) of DIC compared with control. On the other hand, C and AUC of 4-hydroxydiclofenac (4-OHDIC) were decreased after quercetin treatment. In addition, geometric mean ratios and 90% confidence intervals for C and AUC of DIC and 4-OHDIC were both out of the no-effect limits of 0.80-1.25, which indicates a significant pharmacokinetic interaction between quercetin and DIC. Furthermore, quercetin treatment significantly decreased metabolic ratios of C and AUC suggesting that reduced formation of DIC to 4-OHDIC. The results suggest that quercetin might have inhibited CYP2C9-mediated metabolism of DIC. Accordingly, caution should be taken when quercetin is used in combination with therapeutic drugs metabolized by CYP2C9, and dose adjustment of CYP2C9 substrates may be necessary.

Inhibitory Effects of Quercetin and Its Main Methyl, Sulfate, and Glucuronic Acid Conjugates on Cytochrome P450 Enzymes, and on OATP, BCRP and MRP2 Transporters

“…Nevertheless, a milder inhibition regarding CYP2C19-and/or CYP3A4-mediated elimination of certain drugs cannot be excluded, since not only Q but its metabolites can also exert moderate inhibition on these enzymes. This hypothesis is supported by the report of Bedada and Neerati [67] where the administered Q (500 mg twice daily for 10 days) significantly decreased the CYP2C9-mediated elimination of diclofenac in healthy human subjects, despite the observations in a previous in vitro study that Q and some of its conjugates (Q3 S, IR, and tamarixetin) were only weak inhibitors of the enzyme and glucuronides (Q3G and I3G) did not affect CYP2C9 activity [14]. Previous studies showed the similar or stronger interactions of methyl and sulfate metabolites of Q with xanthine oxidase enzyme [68] and human serum albumin [14,69] compared to the parent compound.…”

Interactions of 7,8-Dihydroxyflavone with Serum Albumin as well as with CYP2C9, CYP2C19, CYP3A4, and Xanthine Oxidase Biotransformation Enzymes

“…In the same model applied in this study, casticin was 1.3-fold weaker, while diosmetin was 2.7-fold stronger inhibitor of CYP2C9 enzyme compared to DHF [26,29]. Despite the fact that quercetin and its metabolites proved to be weak inhibitors of CYP2C9-catalyzed diclofenac hydroxylation [25], quercetin (500 mg, administered twice daily) significantly inhibited the metabolism of diclofenac in healthy human volunteers [43]. These observations suggest the potential hazardous consequences of the simultaneous administration of DHF with certain drugs eliminated through CYP2C9.…”

Testing the Pharmacokinetic Interactions of 24 Colonic Flavonoid Metabolites with Human Serum Albumin and Cytochrome P450 Enzymes

“…As it has been reported, flavonoids and their conjugated metabolites interact with serum albumin [5,43,44] and with several biotransformation enzymes [45][46][47][48]. Flavonoids and their conjugated metabolites reach only nanomolar or low micromolar systemic plasma concentrations [49], in contrast to some of the colonic flavonoid metabolites [27].…”