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.