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

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.

Keywords:

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

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was financially supported by the National Natural Science Foundation of China under Grant [81703804].