Abstract

1. l-tetrahydropalmatine (l-THP) is mainly metabolised by CYP450 enzymes.

2. This study was to investigate the possible effect of co-administered CYP inhibitors on the pharmacokinetics of l-THP and its metabolites in rats.

3. 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.

4. With regard to l-THP, the AUC_0–48 were significantly increased by 4.3, 3.79, and 11.39 folds, and C_max 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 AUC_0–48 of 2-DM and 2-DM-Glu by 1.38 ∼ 2.43 times, while C_max was significantly decreased by 41.3 and 78.0% in the ABT group, respectively. The C_max of 3-DM was reduced by 51.38, 48.02, and 63.31% after pre-treatment with KET, QD, and ABT, respectively, and C_max of 3-DM-Glu decreased correspondingly by 29.6, 22.1, and 58.0%.

5. 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.

抽象的

1. 1-延胡索（1- THP）主要由CYP450酶代谢。

2. 本研究旨在探讨共同给予的CYP抑制剂对药代动力学的可能效果1- THP及其主要代谢物。

3. 已建立的LC-MS / MS方法已应用于之间药物-药物相互作用的评价1- THP和CYP抑制剂。以下CYP抑制剂，单剂量给药1- THP（9毫克/千克）口服给予。

4. 至于1- THP中，AUC _0-48分别显著增加4.3，3.79，和11.39倍，和Ç_最大值分别增加了4.74，3.64，和2.76倍酮康唑组（KET），奎尼丁组（QD） ，和1-氨基苯并三唑基（ABT）。KET和QD均使2-DM和2-DM-Glu的AUC _0-48显着增加_1.38〜2.43倍，而ABT组的C _max分别显着下降41.3和78.0％。所述Ç_最大3-DM中的溶液用KET，QD，和ABT，分别与预处理后减少了51.38，48.02，63.31和％Ç_最大 3-DM-Glu的含量分别降低了29.6％，22.1和58.0％。

5. 结果表明，CYP抑制剂可显着影响1- THP及其代谢产物的全身水平。为确保l -THP的安全使用，当l -THP与CYP抑制剂，特别是与CYP3A4和2D6抑制剂共同给药时，应引起注意。