Wu Xiaochun, Li Qing, Xin Huawen, Yu Airong, Zhong Mingyuan
Department of Clinical Pharmacology, Wuhan General Hospital, Wuhan, 430070, China.
Eur J Clin Pharmacol. 2005 Sep;61(8):567-72. doi: 10.1007/s00228-005-0952-3. Epub 2005 Aug 26.
To study the effects of berberine (BBR) on the blood concentration and pharmacokinetics of cyclosporin A (CsA) in renal-transplant recipients.
In a randomized and controlled clinical trial, 52 renal-transplant recipients were treated with CsA and 0.2 g BBR three times daily for 3 months, while another 52 subjects received CsA without BBR co-administration. Blood trough concentration of CsA and biochemistry indexes for hepatic and renal functions were determined. For the pharmacokinetic study, six renal-transplant recipients were included with a 3-mg/kg dosage of CsA twice daily before and after oral co-administration of 0.2 g BBR three times daily for 12 days.
The trough blood concentrations and the ratios of concentration/dose of CsA in the BBR-treated group increased by 88.9% and 98.4%, respectively, compared with those at baseline (P < 0.05). As for the BBR-free group, they rose by 64.5% and 69.4%, respectively, relative to those at baseline (P < 0.01). Nevertheless, the final blood concentrations and the ratios of concentration/dose of CsA in BBR-treated patients were still 29.3% and 27.8%, respectively, higher than those in BBR-free patients (P < 0.05). No significant effects on liver or renal functions were observed under coadministration of BBR. After co-administration of BBR in six patients for 12 days, the mean AUC of CsA was increased by 34.5% (P < 0.05). The mean time taken to reach the peak blood concentration (t(max)) and the mean half-life (t(1/2)) of CsA were increased by 1.7 h and 2.7 h, respectively (P < 0.05). The average percentage increases in the steady-state drug concentration (Css) and minimum blood concentration (Cmin) were 34.5% and 88.3%, respectively (P < 0.05). In addition, the average percentage decrease in CL/F was 40.4% (P < 0.05) and the peak-to-through fluctuation index was significantly reduced (P < 0.01).
The BBR can markedly elevate the blood concentration of CsA in renal-transplant recipients in both clinical and pharmacokinetic studies. This combination may allow a reduction of the CsA dosage. The mechanism for this interaction is most likely explained by inhibition of CYP3A4 by BBR in the liver and/or small intestine.
研究小檗碱（BBR）对肾移植受者中环孢素A（CsA）血药浓度及药代动力学的影响。
在一项随机对照临床试验中，52例肾移植受者接受CsA治疗，同时每日3次服用0.2 g BBR，持续3个月，另外52例受试者仅接受CsA治疗，不联合使用BBR。测定CsA的血药谷浓度以及肝肾功能生化指标。在药代动力学研究中，纳入6例肾移植受者，在每日3次口服0.2 g BBR共12天前后，每日2次给予3 mg/kg剂量的CsA。
与基线相比，BBR治疗组CsA的血药谷浓度及其浓度/剂量比分别升高了88.9%和98.4%（P<0.05）。对于未使用BBR的组，相对于基线，它们分别升高了64.5%和69.4%（P<0.01）。然而，BBR治疗患者中CsA的最终血药浓度及其浓度/剂量比仍分别比未使用BBR的患者高29.3%和27.8%（P<0.05）。联合使用BBR时，未观察到对肝肾功能有显著影响。在6例患者中联合使用BBR 12天后，CsA的平均曲线下面积（AUC）增加了34.5%（P<0.05）。CsA达到血药峰浓度的平均时间（t(max)）和平均半衰期（t(1/2)）分别增加了1.7小时和2.7小时（P<0.05）。稳态药物浓度（Css）和最低血药浓度（Cmin）的平均百分比增加分别为34.5%和88.3%（P<0.05）。此外，清除率/分布容积（CL/F）的平均百分比降低为40.4%（P<0.05），峰谷波动指数显著降低（P<0.01）。
在临床和药代动力学研究中，BBR均可显著提高肾移植受者中CsA的血药浓度。这种联合用药可能允许减少CsA的剂量。这种相互作用的机制很可能是由于BBR在肝脏和/或小肠中对细胞色素P450 3A4（CYP3A）的抑制作用。
