Quercetin‑3‑O‑β‑D‑glucoside decreases the bioavailability of cyclosporin A through regulation of drug metabolizing enzymes, transporters and nuclear receptors in rats

Abstract

Quercetin is a flavonoid compound that is widely present in food and drink. Quercetin-3-O-β-D-glucoside (Q3GA) is a major metabolite of quercetin. The aim of the present study was to investigate the effect of Q3GA on the pharmacokinetics of orally and intravenously administered cyclosporin A (CsA) in rats, and to assess the effect of Q3GA on drug-metabolizing enzymes (DMEs), drug transporters (DTs) and nuclear receptors (NRs). The pharmacokinetic parameters of CsA were measured following oral (10 mg/kg) and intravenous (2.5 mg/kg) administration of CsA in the presence or absence of Q3GA. The mRNA and protein expression levels of DMEs, DTs and NRs in the liver and small intestine were detected by quantitative polymerase chain reaction and western blot analysis. The results indicated that the intravenous administration of Q3GA (2.5, 5 or 10 mg/kg) for 7 consecutive days reduced the bioavailability of oral CsA. By contrast, the pharmacokinetics of the intravenous administration of CsA were not affected by Q3GA. However, the mRNA and protein expression levels of DMEs and DTs were inhibited by Q3GA. The activation of DMEs and DTs by NRs, and the interplay between DMEs and DTs, may explain these results. The present study identified a novel flavonoid-drug interaction, which may have implications for patients taking CsA and quercetin supplements or on a quercetin-containing diet.

Inhibitory effects of quercetin and its major metabolite quercetin‑3‑O‑β‑D‑glucoside on human UDP‑glucuronosyltransferase 1A isoforms by liquid chromatography‑tandem mass spectrometry

“…Quercetin and Q3GA exhibited similar inhibitory effects on the protein and mRNA expression levels of UGT1A1 in the small intestine and the liver. This is consistent with our preliminary data and previously published studies ( 19 , 43 ). It has also been reported that quercetin inhibits glucuronidation of ethanol in human liver microsomes and in recombinant UGT1A1, UGT1A3, UGT 1A4, UGT1A6 and UGT1A9 enzymes ( 44 ).…”

“…However, the underlying mechanisms for these interactions remain unclear. Our previous studies have demonstrated that Q3GA increases the C max , AUC 0-t and AUC 0-∞ of cyclosporine A (19,43). In order to further elucidate the underlying mechanisms of quercetin and Q3GA on the pharmacokinetics of cyclosporine A, the inhibitory effects of quercetin and Q3GA on the enzyme activity of recombinant UGT1A isoforms were investigated in vitro.…”

“…Quercetin-3-O-β-D-glucoside (Q3GA; Fig. 1B ) is one of the primary metabolites found in the blood circulation ( 19 ). Q3GA exerts various pharmacological properties.…”

Effect of Tripterine on the pharmacokinetics of cyclosporine A and its mechanism, in rats

“…The method for the determination of CsA was based on our previous developed LC-MS/MS methods (Yang et al, 2018). The linear concentration range of CsA was 5-4000 ng/mL, and the lower limit of quantification was 5 ng/mL.…”

Distinct effects of calcineurin dependent and independent immunosuppressants on endotoxaemia‐induced nephrotoxicity in rats: Role of androgens

“…The 6‐h post‐LPS period was employed because it has been shown adequate for eliciting well‐defined signs of renal toxicity and inflammation 29‐31 . Further, the administration of immunosuppressants 2 h prior to LPS would allow a total of 8 h before the animal death, which is well within the reported half‐lives of these drugs when administered intravenously, thus maintaining therapeutically relevant blood concentrations of the drugs during the experimentation period 71‐73 . The collected serum was aspirated, divided into aliquots, and stored at −80℃ until used for the colorimetric measurement of creatinine and urea.…”