Pharmacokinetics of Herb-Drug Interactions of Plumbagin and Tazemetostat in Rats by UPLC-MS/MS.

Objective: A sensitive and rapid UPLC-MS/MS method for determination of tazemetostat in rat plasma was developed, and the pharmacokinetics of herb-drug interactions (HDIs) of plumbagin (PLB) and tazemetostat was investigated. Methods: After the rat plasma samples were precipitated by acetonitrile, tazemetostat and verubecestat (ISTD) were detected. Gradient elution was performed with 0.1% formic acid and acetonitrile as mobile phases. The multi-reaction monitoring was used with ESI+ source, and the ion pairs for tazemetostat and ISTD were m/z 573.12→135.99 and m/z 410.10→124.00, respectively. 12 SD rats were randomly divided into the control group and the experimental group, 6 rats in each group. The rats in the experimental group were given PLB 100 mg/kg by gavage once a day for 7 consecutive days. The rats in the control group were given the same amount of 0.1% sodium carboxymethyl cellulose solution by gavage once a day for 7 consecutive days. At the seventh day, tazemetostat (80 mg/kg) was given and the blood was collected at different time points. The main parameters of pharmacokinetics were calculated and the herb-drug interactions (HDIs) were evaluated. Results: In the calibrated range of 1-1000 ng/mL, tazemetostat had a good linearity. The extraction recovery was more than 84%, and the RSD of intra-batch and inter-batch precision were both less than 15%. The Cmax of tazemetostat in the experimental group was 32.48% higher than that in the control group, and the AUC(0-t) and AUC(0-∞) of tazemetostat in the experimental group were 46.24% and 46.67% higher than that in the control group, respectively, and the t1/2 was prolonged from 10.56 h to 11.73 h. Conclusion: A simple, rapid and sensitive UPLC-MS/MS method for the determination of tazemetostat in rat plasma was established. PLB can inhibit the metabolism of tazemetostat and increase the plasma exposure of tazemetostat in rats.

Effect of Chaihu Shugan Pills on the Pharmacokinetics of Duloxetine and its Metabolite 4-Hydroxyduloxetine in Beagle Dogs: A Herb-Drug Interaction Study.

The effect of Chaihu Shugan pills (CHSG) on the pharmacokinetics of duloxetine and its metabolite 4-hydroxyduloxetine in beagle dogs was investigated by establishing an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to simultaneously measure the concentrations of duloxetine and 4-hydroxyduloxetine in beagle dog plasma. Duloxetine and 4-hydroxyduloxetine were separated on the UPLC-C18 column after acetonitrile precipitation and detected by mass spectrometry with multireaction detection mode (MRM). Six adult healthy beagle dogs (weighing 7-9 kg, male and female) were randomly selected and examined for a single-dose administration of duloxetine hydrochloride (2 mg/kg, control group) and oral administration of CHSG (0.3 g/kg) twice daily for 15 consecutive days followed by a single-dose administration of duloxetine hydrochloride (2 mg/kg, experimental group) using the self-control method. All plasma samples were treated in the same way, and then the concentrations of duloxetine and 4-hydroxyduloxetine were determined using the established UPLC-MS/MS method. The obtained data were subjected to DAS 2.0 software to calculate the pharmacokinetic parameters, and SPSS 20.0 software was used to compare the differences between the two groups. Duloxetine and 4-hydroxyduloxetine had a good linear relationship in the ranges of 1-1000 ng/ml and 0.1-100 ng/ml, and the lower limits of quantification (LLOQ) were 1 ng/mL and 0.1 ng/ml, respectively. The precision, accuracy, extraction recovery, matrix effect, and stability meet the requirements of the guiding principles. After combination with CHSG, C max and AUC0⟶t of duloxetine decreased by 49.33% and 13.08%, respectively, and t 1/2 was shortened to 10.17 h; C max and AUC0⟶t of 4-hydroxyduloxetine decreased by 71.47% and 48.78%, respectively, and t 1/2 was shortened to 7.97 h. The UPLC-MS/MS method was fully developed to simultaneously measure the plasma concentration of duloxetine and its metabolite 4-hydroxyduloxetine in beagle dogs. CHSG could slow down the absorption of duloxetine, induce the metabolism of duloxetine and 4-hydroxyduloxetine in beagle dogs, and reduce plasma exposure.