Inhibitory effect of ketoconazole, quinidine and 1-aminobenzotriazole on pharmacokinetics of <i>l-</i>tetrahydropalmatine and its metabolite in rats
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<i>l-</i>tetrahydropalmatine (<i>l-</i>THP) is mainly metabolised by CYP450 enzymes.This study was to investigate the possible effect of co-administered CYP inhibitors on the pharmacokinetics of <i>l-</i>THP and its metabolites in rats.An established LC-MS/MS method has been applied for the evaluation of drug-drug interaction between <i>l-</i>THP and CYP inhibitors. Following the administration of CYP inhibitors, a single dose of <i>l-</i>THP (9 mg/kg) was orally administrated.With regard to <i>l-</i>THP, the AUC<sub>0–48</sub> were significantly increased by 4.3, 3.79, and 11.39 folds, and <i>C</i><sub>max</sub> 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<sub>0–48</sub> of 2-DM and 2-DM-Glu by 1.38 ∼ 2.43 times, while <i>C</i><sub>max</sub> was significantly decreased by 41.3 and 78.0% in the ABT group, respectively. The <i>C</i><sub>max</sub> of 3-DM was reduced by 51.38, 48.02, and 63.31% after pre-treatment with KET, QD, and ABT, respectively, and <i>C</i><sub>max</sub> 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 <i>l</i>-THP and its metabolites. To guarantee the safe use of <i>l</i>-THP, attention should be paid when <i>l</i>-THP was co-administered with CYP inhibitors, particularly with CYP3A4 and 2D6 inhibitors. <i>l-</i>tetrahydropalmatine (<i>l-</i>THP) is mainly metabolised by CYP450 enzymes. This study was to investigate the possible effect of co-administered CYP inhibitors on the pharmacokinetics of <i>l-</i>THP and its metabolites in rats. An established LC-MS/MS method has been applied for the evaluation of drug-drug interaction between <i>l-</i>THP and CYP inhibitors. Following the administration of CYP inhibitors, a single dose of <i>l-</i>THP (9 mg/kg) was orally administrated. With regard to <i>l-</i>THP, the AUC<sub>0–48</sub> were significantly increased by 4.3, 3.79, and 11.39 folds, and <i>C</i><sub>max</sub> 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<sub>0–48</sub> of 2-DM and 2-DM-Glu by 1.38 ∼ 2.43 times, while <i>C</i><sub>max</sub> was significantly decreased by 41.3 and 78.0% in the ABT group, respectively. The <i>C</i><sub>max</sub> of 3-DM was reduced by 51.38, 48.02, and 63.31% after pre-treatment with KET, QD, and ABT, respectively, and <i>C</i><sub>max</sub> 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 <i>l</i>-THP and its metabolites. To guarantee the safe use of <i>l</i>-THP, attention should be paid when <i>l</i>-THP was co-administered with CYP inhibitors, particularly with CYP3A4 and 2D6 inhibitors.
