Influence of quercetin on the pharmacokinetics of ranolazine in rats andin vitromodels

Abstract

The aim of our study was to enhance the bioavailability of ranolazine by using herbal-bioenhancer quercetin in rats and to study the role of P-glycoprotein (P-gp) in vitro models. In single dose study (SDS), rats were divided into four groups, Group I was treated with 0.5% sodium carboxy methyl cellulose (SCMC), Group II was treated with ranolazine (14 mg/kg), Group III was treated with quercetin (20 mg/kg) and Group IV was treated with both ranolazine and quercetin. The blood samples were collected at 0.5, 1, 2, 3, 4, 6, 8 and 12 h, and the concentration of ranolazine in the plasma was estimated by reverse phase high performance liquid chromatography (RP-HPLC) method. In multiple dose study (MDS), rats were treated with same drugs for 7 days. On 8th day, the concentration of ranolazine in plasma was estimated. In vitro study performed on the rat and chick intestinal sacs to study the intestinal transport of ranolazine in the presence and absence of quercetin and verapamil (P-gp-inhibitor). Quercetin increased the peak concentration (Cmax) of ranolazine from 254 ± 8.45 to 324 ± 10.21 and 331 ± 9.65 ng/mL in SDS and MDS, respectively. Quercetin also increased area under the curve (AUC) of ranolazine from 1565.12 ± 52.24 to 2016.98 ± 142.65 and 2070.85 ± 271.60 ng/mL/h in SDS and MDS, respectively. The transport of ranolazine from mucosal side to serosal side was increased in presence of quercetin. Quercetin is an inhibitor of CYP3A4 and P-gp. So it increased the AUC and Cmax of ranolazine.

Quercetin reduced the formation of N‐acetyl‐p‐benzoquinoneimine, a toxic metabolite of paracetamol in rats and isolated rat hepatocytes

“…In the present study, we found that the C max , AUC 0-12 , AUC 0-∞ , t 1/2 , and MRT of orally administered paracetamol were significantly enhanced, and the CL/F, Vz/F, and Vss/F were significantly reduced by co-administration of silymarin (100 mg/kg) and quercetin (10 and 20 mg/kg). These results are consistent with reports by Li and Choi (2009), Kim, Park, andPark (2009), Choi, Jo, and, Challa et al (2013), Babu, Naveen, Haroled, Rajesh, and Jawahar (2013), Shin, Choi, and Li (2006), Choi, Piao, andKang (2011), andCheguri, Ajmera, andCiddi (2017).…”

“…In another study, quercetin significantly increased the plasma concentrations, AUC, C max , and MRT of valsartan, maybe due to inhibition of CYP3A4 and P‐gp (Challa et al, ). Similarly, the bioavailability, AUC, C max , and MRT of ranolazine was enhanced by quercetin in rats due to CYP3A4 and P‐gp inhibition (Babu et al, ). Fexofenadine (a P‐gp substrate) was given to healthy volunteers once daily for 7 days with 500‐mg quercetin or placebo three times a day.…”

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

“…Increasing evidence suggests that Que may interact with numerous xenobiotics. For example, Que has been demonstrated to increase the bioavailability of various drugs, including fexofenadine ( 43 ), rosiglitazone ( 44 ) and CsA ( 33 ) in humans; paclitaxel ( 45 ), valsartan ( 46 ), ranolazine ( 47 ), tamoxifen ( 48 ) and doxorubicin ( 49 ) in rats; and digoxin ( 50 ) in pigs. By contrast, Que decreased the bioavailability of talinolol ( 51 ) in humans, metoprolol ( 52 ) in rats, simvastatin ( 53 ) in pigs and CsA ( 32 , 34 – 36 ) in pigs and rats.…”

Safety Aspects of the Use of Quercetin as a Dietary Supplement

“…Some animal studies with rats, rabbits, or pigs investigated the drug interaction of quercetin as single or repeated doses for several days of 0.6–100 mg quercetin per kg bw per day (in one study up to 300 mg kg –1 bw per day). Increased drug bioavailabilities (increase in AUC and/or in maximum plasma concentration) at least with one of the applied dose regiments were observed with oral intake of irinotecan, etoposide, tamoxifen, paclitaxel, doxorubicin (all anticancer drugs), digoxin (drug against heart insufficiency), verapamil, and diltiazem (calcium channel blockers used in the treatment of hypertension, angina pectoris, and some types of heart arrhythmia), valsartan (antihypertensive drug), ranolazine (drug to treat angina pectoris), and paracetamol . With orally applied pioglitazone (drug to treat type 2 diabetes), an increase in bioavailability (AUC 0‐∞ ) was seen in nondiabetic rats with co‐administration of quercetin, whereas in diabetic rats the increase in AUC did not reach statistical significance .…”