title: 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.
authors: Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors: Yani
authors: Y
authors: Liu
authors: Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors: Xiaomei
authors: X
authors: Luo
authors: Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors: Chunxiao
authors: C
authors: Yang
authors: Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors: Tingyu
authors: T
authors: Yang
authors: Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors: Jiali
authors: J
authors: Zhou
authors: Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
authors: Shaojun
authors: S
authors: Shi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D000975:Antioxidants / Q000494:pharmacology*; D016572:Cyclosporine / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D003879:Dermatologic Agents / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005786:Gene Expression Regulation / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000235:genetics; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics; D011794:Quercetin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D000099148:UGT1A1 Enzyme
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D000975:Antioxidants; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D003879:Dermatologic Agents; D014453:Glucuronosyltransferase; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011794:Quercetin; D012333:RNA, Messenger; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C503597:Slco1a4 protein, rat; C421207:Slco1b2 protein, rat; C479545:Slco3a1 protein, rat; C499946:Ugt1a1 protein, rat; D000099148:UGT1A1 Enzyme; C465260:Cyp3a2 protein, rat; C465138:Cyp3a23-3a1 protein, rat