Inhibitory effect of ketoconazole, quinidine and 1-aminobenzotriazole on pharmacokinetics of l-tetrahydropalmatine and its metabolite in rats

l-tetrahydropalmatine (l-THP) is mainly metabolised by CYP450 enzymes.This study was to investigate the possible effect of co-administered CYP inhibitors on the pharmacokinetics of l-THP and its metabolites in rats.An established LC-MS/MS method has been applied for the evaluation of drug-drug interaction between l-THP and CYP inhibitors. Following the administration of CYP inhibitors, a single dose of l-THP (9 mg/kg) was orally administrated.With regard to l-THP, the AUC0–48 were significantly increased by 4.3, 3.79, and 11.39 folds, and Cmax were increased by 4.74, 3.64, and 2.76 folds in the ketoconazole group (KET), quinidine group (QD), and 1-aminobenzotriazole group (ABT), respectively. KET and QD both significantly increased the AUC0–48 of 2-DM and 2-DM-Glu by 1.38 ∼ 2.43 times, while Cmax was significantly decreased by 41.3 and 78.0% in the ABT group, respectively. The Cmax of 3-DM was reduced by 51.38, 48.02, and 63.31% after pre-treatment with KET, QD, and ABT, respectively, and Cmax of 3-DM-Glu decreased correspondingly by 29.6, 22.1, and 58.0%.Results indicated that CYP inhibitors could markedly influence the systemic level of l-THP and its metabolites. To guarantee the safe use of l-THP, attention should be paid when l-THP was co-administered with CYP inhibitors, particularly with CYP3A4 and 2D6 inhibitors. l-tetrahydropalmatine (l-THP) is mainly metabolised by CYP450 enzymes. This study was to investigate the possible effect of co-administered CYP inhibitors on the pharmacokinetics of l-THP and its metabolites in rats. An established LC-MS/MS method has been applied for the evaluation of drug-drug interaction between l-THP and CYP inhibitors. Following the administration of CYP inhibitors, a single dose of l-THP (9 mg/kg) was orally administrated. With regard to l-THP, the AUC0–48 were significantly increased by 4.3, 3.79, and 11.39 folds, and Cmax were increased by 4.74, 3.64, and 2.76 folds in the ketoconazole group (KET), quinidine group (QD), and 1-aminobenzotriazole group (ABT), respectively. KET and QD both significantly increased the AUC0–48 of 2-DM and 2-DM-Glu by 1.38 ∼ 2.43 times, while Cmax was significantly decreased by 41.3 and 78.0% in the ABT group, respectively. The Cmax of 3-DM was reduced by 51.38, 48.02, and 63.31% after pre-treatment with KET, QD, and ABT, respectively, and Cmax of 3-DM-Glu decreased correspondingly by 29.6, 22.1, and 58.0%. Results indicated that CYP inhibitors could markedly influence the systemic level of l-THP and its metabolites. To guarantee the safe use of l-THP, attention should be paid when l-THP was co-administered with CYP inhibitors, particularly with CYP3A4 and 2D6 inhibitors.

左旋四氢帕马丁（l-tetrahydropalmatine, l-THP）主要经细胞色素P450酶（CYP450 enzymes）代谢。本研究旨在考察联用CYP抑制剂对大鼠体内左旋四氢帕马丁及其代谢产物药代动力学的潜在影响。本研究采用已建立的液相色谱-串联质谱法（LC-MS/MS），评估左旋四氢帕马丁与CYP抑制剂间的药物相互作用。在给予CYP抑制剂后，大鼠单次口服给予9 mg/kg的左旋四氢帕马丁。针对左旋四氢帕马丁而言，酮康唑（KET）组、奎尼丁（QD）组及1-氨基苯并三唑（ABT）组的0~48小时血药浓度-时间曲线下面积（AUC0–48）分别显著升高4.3倍、3.79倍及11.39倍，血药峰浓度（Cmax）分别升高4.74倍、3.64倍及2.76倍。酮康唑与奎尼丁均可使2-DM及2-DM-Glu的AUC0–48显著升高1.38~2.43倍，而1-氨基苯并三唑组的Cmax分别显著降低41.3%与78.0%。经酮康唑、奎尼丁及1-氨基苯并三唑预处理后，3-DM的Cmax分别降低51.38%、48.02%及63.31%，3-DM-Glu的Cmax则相应分别降低29.6%、22.1%及58.0%。研究结果表明，CYP抑制剂可显著影响左旋四氢帕马丁及其代谢产物的全身暴露水平。为保障左旋四氢帕马丁的安全用药，当其与CYP抑制剂联用时需格外注意，尤其是与CYP3A4及2D6抑制剂联用时。
左旋四氢帕马丁（l-tetrahydropalmatine, l-THP）主要经细胞色素P450酶（CYP450 enzymes）代谢。本研究旨在考察联用CYP抑制剂对大鼠体内左旋四氢帕马丁及其代谢产物药代动力学的潜在影响。本研究采用已建立的液相色谱-串联质谱法（LC-MS/MS），评估左旋四氢帕马丁与CYP抑制剂间的药物相互作用。在给予CYP抑制剂后，大鼠单次口服给予9 mg/kg的左旋四氢帕马丁。针对左旋四氢帕马丁而言，酮康唑（KET）组、奎尼丁（QD）组及1-氨基苯并三唑（ABT）组的0~48小时血药浓度-时间曲线下面积（AUC0–48）分别显著升高4.3倍、3.79倍及11.39倍，血药峰浓度（Cmax）分别升高4.74倍、3.64倍及2.76倍。酮康唑与奎尼丁均可使2-DM及2-DM-Glu的AUC0–48显著升高1.38~2.43倍，而1-氨基苯并三唑组的Cmax分别显著降低41.3%与78.0%。经酮康唑、奎尼丁及1-氨基苯并三唑预处理后，3-DM的Cmax分别降低51.38%、48.02%及63.31%，3-DM-Glu的Cmax则相应分别降低29.6%、22.1%及58.0%。研究结果表明，CYP抑制剂可显著影响左旋四氢帕马丁及其代谢产物的全身暴露水平。为保障左旋四氢帕马丁的安全用药，当其与CYP抑制剂联用时需格外注意，尤其是与CYP3A4及2D6抑制剂联用时。