Liu Ruijuan, Li Xia, Wei Jingyao, Liu Shuaibing, Chang Yuanyuan, Zhang Jiali, Zhang Ji, Zhang Xiaojian, Fuhr Uwe, Taubert Max, Tian Xin
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou, China.
Front Pharmacol. 2019 May 14;10:518. doi: 10.3389/fphar.2019.00518. eCollection 2019.
Despite its narrow therapeutic window and large interindividual variability, cyclosporine A (CsA) is the first-line therapy following organ transplantation. Metabolized mainly by CYP3A and being a substrate of P-glycoprotein (P-gp), CsA is susceptible to drug-drug interactions. Baicalin (BG) is a drug used for adjuvant therapy of hepatitis in traditional Chinese medicine. Since its aglycone baicalein (B) inhibits CYP3A and P-gP, co-administration might affect CsA pharmacokinetics. This study investigated the effect of BG on CsA pharmacokinetics. In a two-period study, 16 healthy volunteers received a single 200 mg oral CsA dose alone (reference period) or in combination with 500 mg BG (test period). Pharmacokinetic evaluation of CsA was carried out using non-compartmental analysis (NCA) and population pharmacokinetics (popPK). Treatments were compared using the standard bioequivalence method. Based on NCA, 90% CIs of AUC and test-to-reference ratios were within bioequivalence boundaries. In the popPK analysis, a two-compartment model (clearance/F 62.8 L/h, central and peripheral volume of distribution/F 254 L and 388 L) with transit compartments for absorption appropriately described CsA concentrations. No clinically relevant effect of 500 mg BG co-administration on CsA pharmacokinetics was identified and both treatments were well tolerated.
尽管环孢素A（CsA）治疗窗狭窄且个体差异大，但仍是器官移植后的一线治疗药物。CsA主要由CYP3A代谢，是P-糖蛋白（P-gp）的底物，易发生药物相互作用。黄芩苷（BG）是一种用于中医辅助治疗肝炎的药物。由于其苷元黄芩素（B）抑制CYP3A和P-gP，联合用药可能会影响CsA的药代动力学。本研究调查了BG对CsA药代动力学的影响。在一项两阶段研究中，16名健康志愿者单独接受单次200mg口服CsA剂量（参照阶段）或联合500mg BG（试验阶段）。使用非房室分析（NCA）和群体药代动力学（popPK）对CsA进行药代动力学评估。采用标准生物等效性方法比较治疗效果。基于NCA，AUC的90%置信区间和试验与参照比值在生物等效性界限内。在popPK分析中，具有吸收转运室的二室模型（清除率/F 62.8L/h，中央和外周分布容积/F 254L和388L）能恰当描述CsA浓度。未发现联合使用500mg BG对CsA药代动力学有临床相关影响，且两种治疗耐受性良好。
