Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacs in vitro
Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacs in vitro
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DOI：
10.3109/03639045.2013.819885
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发表时间：
2014-10-01
影响因子：
3.4
通讯作者：
Babu, K. Naveen
中科院分区：
文献类型：
--
作者：
Sandeep, M. Surya;Sridhar, V.;Babu, K. Naveen
研究柚皮素对非洛地平在大鼠体内药代动力学（PK）和体外大鼠外翻肠囊膜通透性的影响。大鼠同时给予非洛地平10 mg/kg， p.o.和柚皮素（25、50和100 mg/kg， p.o.），连续15 d。对照组大鼠给予相应体积的载药。单剂量PK组（SDS）和多剂量PK组（MDS）分别于第1天和第15天从眶后神经丛采血。采用热力学方法计算PK参数。柚皮素联合给药可显著提高非洛地平的C-max和AUC(total)，且呈剂量依赖性。柚皮素100 mg/kg时，非洛地平在SDS和MDS中的C-max分别从173.25 +/- 14.65和223.26 +/- 26.35增加到561.32 +/- 62.53 ng/mL。非洛地平在SDS和MDS上的AUC（总AUC）分别从2050.48 +/- 60.57和3276.51 +/- 325.61增加到7265.25 +/- 536.11 (ng/mL/h)，显著（p < 0.001）升高。柚皮素和利托那韦（标准p -糖蛋白（P-gp）和细胞色素P450 (CYP)3A4抑制剂）存在时，非洛地平的通透性增加。非洛地平是CYP3A4的底物，柚皮素被报道是P-gp和CYP3A4的调节剂。这些结果表明，柚皮素显著提高非洛地平的C-max和AUC是由于P-gp和CYP3A4的抑制作用。
The aim of this study was to investigate the effect of naringenin on the pharmacokinetics (PK) of felodipine in rats and membrane permeability across rat everted gut sacs in vitro. Rats were simultaneously co-administered with felodipine 10 mg/kg, p.o. and naringenin (25, 50 and 100 mg/kg, p.o.) for 15 consecutive days. Rats of the control groups received the corresponding volume of vehicle. Blood samples were withdrawn from retro-orbital plexus on first day in single dose PK study (SDS) and on 15th day in multiple dosing PK study (MDS). The PK parameters were calculated using Thermo kinetica. The co-administration of naringenin significantly elevated the C-max and increased the AUC(total) of felodipine in dose-dependent manner. The C-max of felodipine was increased from 173.25 +/- 14.65 to 275.61 +/- 44.62 and 223.26 +/- 26.35 to 561.32 +/- 62.53 ng/mL in SDS and MDS, respectively, at the dose of naringenin 100 mg/kg. The AUC(total) of felodipine was significantly (p < 0.001) increased from 2050.48 +/- 60.57 to 3650.22 +/- 78.61 and 3276.51 +/- 325.61 to 7265.25 +/- 536.11 (ng/mL/h) in SDS and MDS, respectively. The permeability of felodipine was increased in presence of naringenin and ritonavir (standard P-glycoprotein (P-gp) and Cytochrome P450 (CYP)3A4 inhibitor). Felodipine is a substrate of CYP3A4, and naringenin was reported to be a modulator of P-gp and CYP3A4. These results suggest that naringenin significantly increased the C-max and AUC of felodipine is due to P-gp and CYP3A4 inhibition.