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

作者：Xiao, Weibin; Deng, Zhirong; Lai, Chongfa; Lu, Haoyang; Huang, Mutu; Wen, Yuguan; Shi, Lei^*

来源：Xenobiotica; the fate of foreign compounds in biological systems, 2021, 51(4): 447-454.

DOI：10.1080/00498254.2020.1867928

• l-tetrahydropalmatine
• CYP450 inhibitors
• drug-drug interactions
• LC-MS/MS
• pharmacokinetics

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 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 similar to 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%. @@@ 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.

• 单位
  广东药学院; 广州医学院; 南方医科大学