The Enantioselective Pharmacokinetic Study Of Desvenlafaxine Sustained Tablet In Chinese Healthy Male Volunteers After Oral Administration

Background Desvenlafaxine(DVS) is the major metabolite of venlafaxine??a second generation of antidepressants. The molecule of DVS contains a chiral center and it is administered clinically as a racemic mixture. DVS mainly inhibits the reuptake of serotonin and norepinephrine, and partially inhibits the reuptake of dopamine, and thus play a role of resisting depression. DVS shows no obvious affinity with adrenergic, cholinergic or H1-histaminergic receptors, leading to less adverse reactions and better safety. Since it is administered orally once a day, DVS has a better patient compliance. The above advantages make DVS a first-line drug for the treatment of adult patients with major depressive disorder(MDD). There has been enantiomer pharmacokinetic studies about oral dose of desvenlafaxine abroad, but there was no any report on the enantioselective pharmacokinetics study of DVS in healthy Chinese volunteers after oral administration at present.Objectives A rapid, sensitive and convenient high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS) method was developed for the determination of desvenlafaxine enantiomers in human plasma. The method was applied in a stereoselective pharmacokinetics study of desvenlafaxine sustained tablet in healthy Chinese volunteers after oral administration.Methods The enantiomers of DVS were extracted from plasma using liquid-liquid extraction with ethylacetate under alkaline conditions, d6-desvenlafaxine was used as internal standard. Chromatographic separation was achieved on an Astec ChirobioticTM V chiral column(150 mm × 4.6 mm, 5 μm) using methanol: 500 mmol·L?1 ammonium formate: formic acid: 1% ammonia(100: 5‰: 0.05‰: 0.05‰, v/v) as the mobile phase, which was delivered at a flow rate of 0.6 mL·min?1. The inject volume was 5.0 μL and a total chromatographic run time of 10 min was achieved. The TSQ Quantum Vantage triple quadrupole mass spectrometric equipped with Heat Electrospray Ionization(HESI) was performed in the positive selective reaction monitoring(SRM) mode using the transitions of m/z 264 â†' 58,107 for DVS enantiomers and m/z 270 â†' 64 for d6-desvenlafaxine.Results Calibration curve was linear over the concentration range of 0.500~150 ng·mL?1 for DVS enantiomers, and the lower limit of quantification was 0.500 ng·mL?1. The intra- and inter-day precision were less than 6.8%, the accuracy was ?5.3~2.9% for the two enantiomers, within the acceptable limit across all concentrations. The total chromatographic run time was 10 min, the baseline separation was achieved, resolution was 1.65. The method was successfully applied for a stereoselective pharmacokinetics study in 12 healthy male Chinese volunteers after an oral dose of 100 mg DVS sustained release tablets. The results proved that both enantiomers shown similar pharmacokinetic parameters in Chinese healthy volunteers.Conclusions A chiral LC-MS/MS method was established and completly validated for the determination of desvenlafaxine enantiomer in human plasma. The method was sensitive and selective and was successfully applied to a stereoselective pharmacokinetic study of desvenlafaxine succinate extended release tablets in human.