Simultaneous quantification of vortioxetine, carvedilol and its active metabolite 4-hydroxyphenyl carvedilol in rat plasma by UPLC-MS/MS: Application to their pharmacokinetic interaction study.

To establish a rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the determination of vortioxetine, carvedilol and its metabolite 4-hydroxyphenyl carvedilol in rat plasma. The analytes and the internal standard (diazepam) were separated on an Acquity UPLC BEH C18 chromatography column (2.1mm×50mm, 1.7µm) using gradient elution with a mobile phase of acetonitrile and 0.1% formic acid in water at a flow rate of 0.4mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 299.2→150.1 for vortioxetine, m/z 407.2→100.3 for carvedilol, m/z 423.2→100.1 for 4-hydroxyphenyl carvedilol and m/z 285.2→193.1 for diazepam (IS) using a positive electrospray ionization interface. The method was validated over a concentration range of 0.5-100ng/mL for vortioxetine, 0.5-1000ng/mL for carvedilol and 0.1-50ng/mL for 4-hydroxyphenyl carvedilol. Total time for each chromatograph was 3.0min. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels exhibited relative standard deviations (RSD)<11.6% and the accuracy values ranged from -12.2% to 11.3%. The analytical method was successfully applied to a pharmacokinetic interaction study of vortioxetine and carvedilol after oral administration vortioxetine and carvedilol in rats. Results suggested that the co-administration of vortioxetine and carvedilol results in a significant drug interaction in rats.

Determination of Apremilast in Rat Plasma by UPLC-MS-MS and Its Application to a Pharmacokinetic Study.

A rapid, sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) was developed and validated for the determination and pharmacokinetic investigation of apremilast in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2 mL of acetonitrile to a 0.1 mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.0 min, and the elution of apremilast was at 1.27 min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring mode using the respective transitions m/z 461.3 → 257.1 for apremilast and m/z 237.2 → 194.2 for carbamazepine (internal standard). The calibration curve was linear over the range of 0.1-100 ng/mL with a lower limit of quantitation of 0.1 ng/mL. The mean recovery of apremilast in plasma was in the range of 83.2-87.5%. Both intraday and interday precision were <9.6%. This method was successfully applied in the pharmacokinetic study after oral administration of 6.0 mg/kg apremilast in rats.

Determination of parthenolide in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study.

A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination and pharmacokinetic investigation of parthenolide in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2mL of acetonitrile containing 30ng/mL of pirfenidone (IS), and to a 0.1mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.0min and the elution of parthenolide was at 1.33min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring (MRM) mode using the respective transitions m/z 249.2→231.1 for parthenolide and m/z 186.2→92.1 for pirfenidone (IS), respectively. The calibration curve was linear over the range of 2.0-500ng/mL with a lower limit of quantitation (LLOQ) of 2.0ng/mL. Mean recovery of parthenolide in plasma was in the range of 78.2-86.6%. Intra-day and inter-day precision were both <8.3%. This method was successfully applied in pharmacokinetic study after oral and intravenous administration of parthenolide in rats.

Effects of Evodiamine on the Pharmacokinetics of Dapoxetine and Its Metabolite Desmethyl Dapoxetine in Rats.

The objective of this work was to investigate the effect of orally administered evodiamine on the pharmacokinetics of dapoxetine and its active metabolite desmethyl dapoxetine in rats. Twelve healthy male Sprague-Dawley rats were randomly divided into 2 groups: the control group (received oral 10 mg/kg dapoxetine alone) and the combination group (10 mg/kg dapoxetine orally co-administered with 100 mg/kg evodiamine). The plasma concentration of dapoxetine and desmethyl dapoxetine were estimated by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and different pharmacokinetic parameters were calculated using the Drug and Statistics 2.0 software. Compared to the control group, the pharmacokinetic parameter of t1/2, AUC(0-∞) and Tmax of dapoxetine in combination group was significantly increased by 63.3% (p < 0.01), 44.8% (p < 0.01) and 50.4% (p < 0.01), respectively. Moreover, evodiamine had significantly decreased the pharmacokinetic parameter of t1/2 and AUC(0-∞) of desmethyl dapoxetine. This study demonstrated that evodiamine inhibits the metabolism of dapoxetine. Henceforth, the pharmacodynamic influence of this interaction should be taken into consideration while prescribing dapoxetine to the patients already taking evodiamine.