The Herb-Drug Pharmacokinetic Interaction of Fluoxetine and Its Metabolite Norfluoxetine with a Traditional Chinese Medicine in Rats by LC-MS/MS

BACKGROUND: Fluoxetine (FLU) is the first-line and widely used medication for depression. The combination of Chaihu Shugan san (CSGS) and FLU is commonly used to enhance antidepressant effects and reduce side effects. OBJECTIVE: The primary objective of this study was to investigate the potential pharmacokinetic effect of CSGS on FLU. MATERIALS AND METHODS: Thirty-two healthy adult male Sprague-Dawley (SD) rats were randomly divided into four groups, the fluoxetine group and multiple dose groups A, B, and C. The rats in the different groups were orally administered with a combination of FLU and different doses of CSGS for 14 d. On the fifteenth day, serial blood samples were taken from the caudal vein before the administration and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 h after the administration. A liquid-liquid extraction method was applied to extract the analytes from serum. Then, the concentrations of FLU and its metabolite, norfluoxetine (NOF), were determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by DAS 3.2.8 program and compared by statistic analysis. RESULTS: Compared with the FLU group, the FLU and NOF area under the plasma concentration-time curve (AUC) (0-∞) in multiple dose group C was significantly increased, while the NOF AUCs (0-∞) in multiple dose group A and multiple dose group B were decreased. Compared with the FLU group, the NOF clearance (CL) in multiple dose group C was decreased, while the CL in multiple dose groups A and B was increased. DISCUSSION AND CONCLUSION: There were some differences in pharmacokinetic parameters between the FLU group and multiple dose groups, and CSGS can affect the pharmacokinetics of fluoxetine.