Baicalin reduces ciclosporin bioavailability by inducing intestinal p-glycoprotein in rats
Baicalin reduces ciclosporin bioavailability by inducing intestinal p-glycoprotein in rats
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黄芩苷通过诱导大鼠肠道 p-糖蛋白降低环孢素生物利用度
DOI：
10.1111/jphp.13067
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发表时间：
2019
影响因子：
3.3
通讯作者：
Zhang Xiaojian
中科院分区：
文献类型：
--
作者：
Tian Xin;Chang Yuanyuan;Wei Jingyao;Liu Ruijuan;Wang Li;Zhang Ji;Zhang Xiaojian
目的探讨不同剂量黄芩苷(BG)对环孢素(CsA)在大鼠体内药代动力学的影响及其可能机制。或静脉注射)对有无BG(80 mg/kg，i.g.或静脉注射)七天。分离大鼠肝脏和肠段，分析细胞色素P3A和P-糖蛋白的表达。采用大鼠外翻肠囊模型，研究了BG对CsA肠道吸收行为的影响。但BG(80 mg/kg，i.g，7d)可使口服CsA的Cmax、AUC0-t和AUC0-∞分别降低38%、26%和25%(P<；0.01或P<；0.05)。进一步研究发现，灌胃多剂量BG后，大鼠肠道P-gp表达增加。体外外翻大鼠肠囊模型显示，BG(10μm)显著降低CsA(10μm)在大鼠肠道的吸收(P<；0.05)。结论多剂量BG可显著降低CsA在大鼠体内的口服生物利用度，其机制可能与抑制CsA在肠道的吸收和诱导P-gp有关。BG与CsA长期合用时，可能发生BG与CsA的相互作用。临床上可能需要调整CsA的剂量和监测血药浓度。
ObjectivesTo investigate the effects of multiple doses of baicalin (BG) on the pharmacokinetics of ciclosporin (CsA) in rats and the potential mechanisms.MethodsPharmacokinetic parameters of CsA were determined in male rats after administration of CsA (3 mg/kg, i.g. or i.v.) to rats in the presence and absence of BG (80 mg/kg, i.g. or i.v.) for 7 days. The livers and intestines of rats were isolated and the CYP3A and p-glycoprotein (P-gp) expression were analysed. The effect of BG on the intestinal absorptive behaviour of CsA was also investigated using in-vitro everted rat gut sac model.Key findingsBaicalin (80 mg/kg, i.v., 7 days) had no effect on the intravenously administered CsA. However, BG (80 mg/kg, i.g., 7 days) significantly decreased theCmax, AUC0–tand AUC0–∞of orally administered CsA by 38, 26 and 25%, respectively (P< 0.01 orP< 0.05). Further study revealed that the expression of P-gp in intestine increased in oral multiple doses of BG-treated rats. The in-vitro everted rat gut sac model demonstrated BG (10 μm) significantly decreased the absorption of CsA (10 μm) in intestine (P< 0.05).ConclusionsMultiple doses of BG decreased the oral bioavailability of CsA in rats significantly, which may be mainly attributable to inhibition of absorption of CsA in intestine and induction of P-gp. The interaction between BG and CsA may occur when BG and CsA were co-administered for long-term use. The dosage adjustment and blood concentration monitoring of CsA may be required in clinic.