Xu Bei-Bei, Xu Zhi-Sheng, Zheng Shuang-Li, Tang Cong-Rong
Wenzhou People's Hospital, Wenzhou, China.
The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Pharmazie. 2014 Jan;69(1):43-7.
Colchicine (COL), an alkaloid derived from plants, has been used to treat gout, pseudogout and familial Mediterranean fever for several decades. The purpose of this study was to investigate the in vivo effect of COL on rat cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19 and CYP2D6) to assess its potential to interact with co-administered drugs. This was a randomized, double-blind, two-way crossover study with a 4-week washout period between the phases. Rats received COL via an irrigation stomach needle at a dose of 0.4 mg/kg once daily for consecutive 10 days. On the eleventh day, a cocktail solution at a dose of 4 ml/kg, which contained phenacetin (15.0 mg/kg), tolbutamide (3.0 mg/kg), omeprazole (15.0 mg/kg) and dextromethorphan (15.0mg/kg), was oral administered to all rats. Then 0.3 ml blood samples were collected at a set of time-points. The plasma concentrations of probe drugs were simultaneously determined by HPLC-MS/MS. Pharmacokinetic parameters simulated by DAS software were used for the evaluation of COL on the activities of rat CYP1A2, CYP2C9, CYP2C19 and CYP2D6 enzymes. Our study showed that COL administration induced CYP2C9 activity, causing a significant decrease in AUC(0-infinity) (P < 0.01) and t1/2 (P < 0.05) of tolbutamide, and a distinct increase in CL (P<0.01). Many pharmacokinetic parameters of dextromethorphan in COL-treated rats were affected significantly, which indicated that the metabolism of dextromethorphan in these treatment groups was evidently slowed down. However, there was no significant influence of pharmacokinetic parameters of phenacetin and omeprazole in COL-treated rats. The results from the present in vivo study suggested that COL showed no effects on rat CYP1A2 and CYP2C19, however, it demonstrated potential inductive effects on CYP2C9 and inhibitory effects on CYP2D6. Therefore, caution is needed when COL is co-administered with drugs metabolized by CYP2C9 or CYP2D6, which may result in altered plasma concentrations of these drugs and relevant drug-drug interactions.
秋水仙碱（COL）是一种从植物中提取的生物碱，几十年来一直用于治疗痛风、假性痛风和家族性地中海热。本研究的目的是调查COL对大鼠细胞色素P450酶（CYP1A2、CYP2C9、CYP2C19和CYP2D6）的体内作用，以评估其与联合给药药物相互作用的可能性。这是一项随机、双盲、双向交叉研究，各阶段之间有4周的洗脱期。大鼠通过灌胃针以0.4mg/kg的剂量连续10天每天接受一次COL。在第11天，给所有大鼠口服剂量为4ml/kg的混合溶液，其中含有非那西丁（15.0mg/kg）、甲苯磺丁脲（3.0mg/kg）、奥美拉唑（15.0mg/kg）和右美沙芬（15.0mg/kg）。然后在一组时间点采集0.3ml血样。通过HPLC-MS/MS同时测定探针药物的血浆浓度。用DAS软件模拟的药代动力学参数用于评估COL对大鼠CYP1A2、CYP2C9、CYP2C19和CYP2D6酶活性的影响。我们的研究表明，给予COL可诱导CYP2C9活性，导致甲苯磺丁脲的AUC(0-∞)（P<0.01）和t1/2（P<0.05）显著降低，CL显著升高（P<0.01）。COL处理组大鼠中右美沙芬的许多药代动力学参数受到显著影响，这表明这些处理组中右美沙芬的代谢明显减慢。然而，COL处理组大鼠中非那西丁和奥美拉唑的药代动力学参数没有显著影响。本体内研究结果表明，COL对大鼠CYP1A2和CYP2C19没有影响，然而，它对CYP2C9有潜在诱导作用，对CYP2D6有抑制作用。因此，当COL与由CYP2C9或CYP2D6代谢的药物联合使用时需要谨慎，这可能导致这些药物的血浆浓度改变以及相关的药物相互作用。
