Impact of quercetin-induced changes in drug-metabolizing enzyme and transporter expression on the pharmacokinetics of cyclosporine in rats

Abstract

The aim of the present study was to evaluate whether quercetin (Que) modulates the mRNA and protein expression levels of drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in the small intestine and liver, and thus modifies the pharmacokinetic profile of cyclosporine (CsA) in rats. This two-part study evaluated the pharmacokinetic profiles of CsA in the presence or absence of Que (experiment I) and the involvement of DMEs and DTs (experiment II). In experiment I, 24 rats received single-dose CsA (10 mg/kg) on day 1, single-dose Que (25, 50 and 100 mg/kg/day; eight rats in each group) on days 3–8, and concomitant CsA/Que on day 9. In experiment II, the mRNA and protein expression levels of cytochrome P (CYP)3A1, CYP3A2, UDP glucuronosyltransferase family 1 member A complex locus, organic anion-transporting polypeptide (OATP)2B1, OATP1B2, P-glycoprotein, breast cancer resistance protein, and multidrug resistance-associated protein 2 in the small intestine and liver of rats were analyzed following oral administration of Que at 25, 50 and 100 mg/kg in the presence or absence of CsA (10 mg/kg) for seven consecutive days. Co-administration of Que (25,50 and 100 mg/kg) decreased the maximum serum concentration of CsA by 46, 50 and 47% in a dose-independent manner. In addition, the area under the curve to the last measurable concentration and area under the curve to infinite time were decreased, by 21 and 16%, 30 and 33%, and 33 and 34% (P<0.01), respectively. However, the mRNA and protein expression levels of the above-mentioned DMEs and DTs were inhibited by Que in a dose-dependent manner (P<0.01) to a similar extent in the small intestine and liver. It was demonstrated that Que was able to reduce the bioavailability of CsA following multiple concomitant doses in rats. Overlapping modulation of intestinal and hepatic DMEs and DTs, as well as the DME-DT interplay are potential explanations for these observations.

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

“…Q3GA exerted a similar effect on the mRNA and protein expression levels. These results were consistent with our previous report about the regulation of DMEs and DTs by quercetin ( 28 ).…”

“…Therefore, the Q3GA co-administration exerted a marked effect on the pharmacokinetics of CsA. These results were consistent with our previous report that the oral administration of quercetin for 7 consecutive days reduced the bioavailability of CsA in rats ( 28 ). Yu et al ( 33 ) and Hsiu et al ( 37 ) reported the same results.…”

“…Our previous study demonstrated that quercetin reduces the bioavailability of CsA following multiple concomitant doses in rats, and regulates the DMEs and DTs in the liver and small intestine ( 28 ). Further research is required to determine the effect of Q3GA on the pharmacokinetics of CsA and on DMEs, DTs and NRs in the liver and small intestine.…”

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 ).…”

Pharmacokinetics of Marbofloxacin Following Oral Administration in Piperine, Quercetin Alone and Both in Combination Pretreated Broiler Chickens

“…Piperine treatment had shown to increase the oral bioavailability of various antibacterial drugs like pefloxacin (Madhukar et al, 2008), gatifloxacin (Patel et al, 2011), amoxicillin (Barve and Ruparel, 2015) and rifampicin (Singh et al, 2018). Quercetin, a flavonoid compound present in many plants and foods could also competitively inhibit the drug metabolizing enzyme CYP3A4 (Choi et al, 2011) and the members of MDR family MDR1, MRP2 and BCRP (Liu et al, 2016). Quercetin treatment had also shown to increase the bioavailability of ciprofloxacin in rat (Devi et al, 2016).…”