Hollow-fiber liquid-phase microextraction and chiral LC-MS/MS analysis of venlafaxine and its metabolites in plasma.

BACKGROUND: An enantioselective analytical method was developed and validated for determination of venlafaxine and its metabolites O-desmethylvenlafaxine and N-desmethylvenlafaxine in plasma samples. The method employed LC-MS/MS analysis and hollow-fiber liquid-phase microextraction (HF LPME) for sample preparation. RESULTS: After HF LPME optimization the following condition was established: sample volume of 4 ml, sample agitation at 1750 rpm, 20 min of extraction, 0.1 mol/l acetic acid as acceptor phase, 1-octanol as organic phase and donor phase pH adjustment to 10. Under these conditions, the method was linear over the concentration range of 5-500 ng/ml with quantification limits of 5 ng/ml. CONCLUSION: The use of HF LPME for sample preparation provided suitable recoveries, efficient clean-up and low consumption of organic solvent.

The effect of dose titration and dose tapering on the tolerability of desvenlafaxine in women with vasomotor symptoms associated with menopause.

OBJECTIVE: To determine whether titrating up and tapering down of desvenlafaxine (administered as desvenlafaxine succinate) improves its tolerability in postmenopausal women with vasomotor symptoms (VMS). METHODS: In the 1-week titration phase, participants received desvenlafaxine 100 mg/d (no titration), desvenlafaxine 50 mg/d, desvenlafaxine 25 mg/d (4 days) then 50 mg/d (3 days), or desvenlafaxine 25 mg/d. Participants then received open-label desvenlafaxine 100 mg/d for 15 weeks. In the 2-week taper phase, participants received placebo, desvenlafaxine 50 mg/d then placebo (7 days each), desvenlafaxine 50 mg/d then 25 mg/d (7 days each), or desvenlafaxine 50 mg/d every other day. Primary endpoints included nausea incidence during the first 2 weeks of treatment and Discontinuation-Emergent Signs and Symptoms (DESS) Checklist total scores after taper weeks 1 and 2. RESULTS: Nausea incidence was significantly lower for the desvenlafaxine 25 mg/d (19%) and 50 mg/d (22.6%) titration regimens vs. no titration (35.2%; p=0.004 and p=0.035, respectively). At taper week 1, mean DESS scores were significantly lower for desvenlafaxine 50 mg every other day (2.26, p<0.001), 50/25 mg/d (2.28, p<0.001), and 50 mg/d-placebo (1.84, p<0.001) taper regimens vs. no taper (7.07). At week 2, the mean DESS total score was significantly higher for the desvenlafaxine 50 mg/d-placebo regimen vs. no taper (4.46 vs. 2.44, respectively; p=0.009). Desvenlafaxine 50 mg every other day was the least tolerated of the taper regimens. CONCLUSIONS: Titration regimens may improve tolerability of desvenlafaxine 100 mg/d in postmenopausal women with VMS. Taper regimens of desvenlafaxine 50 mg/d-placebo or 50/25-mg/d, were better tolerated than abrupt discontinuation or desvenlafaxine 50 mg given every other day taper regimen.

Simultaneous measurement of venlafaxine and its major metabolite, oxydesmethylvenlafaxine, in human plasma by high-performance liquid chromatography with coulometric detection and utilisation of solid-phase extraction.

Venlafaxine, oxydesmethylvenlafaxine and an internal standard (paroxetine) were extracted from plasma by a solid-phase extraction technique. Chromatography was performed using isocratic reversed-phase high-performance liquid chromatography (HPLC) with coulometric endpoint detection. The standard curves were linear over the range 0-200 ng/ml for both venlafaxine and oxydesmethylvenlafaxine in plasma. The mean inter- and intra-assay coefficients of variation over the range of the standard curves were less than 10%. The absolute recovery averaged 74% for venlafaxine and 67% for oxydesmethylvenlafaxine. The sensitivity was 0.5 ng for both the analytes. Plasma profiles of the analytes following oral administration of venlafaxine, are presented.

Analysis of venlafaxine by capillary zone electrophoresis.

Capillary electrophoresis has been used for the separation of venlafaxine and two of its impurities deriving from the synthesis process. The electrophoretic experiments were performed using background electrolytes at different pHs in the 2.5-9.2 range in order to study the effective mobilities and resolution of the three examined compounds. The optimum experimental conditions for the baseline resolution of the three analytes was found at pH 6.5. Very good repeatability for both migration time and corrected peak areas was achieved. The calibration curve was studied for venlafaxine (concentration range 26-224 micrograms/mL), and the plot of the peak area ratio (sample/internal standard [IS]) versus venlafaxine concentration was linear with a correlation coefficient of 0.9991. The effect of different cyclodextrins (CDs), namely, gamma-cyclodextrin (gamma-CD), hydroxypropyl-beta-CD (HP-beta-CD), and alpha-cyclodextrin (alpha-CD), on effective mobility and enantiomeric resolution (R) of venlafaxine (Wy45030) and its impurities (imp1 and imp2) was studied at different pHs, and the best results were obtained at pH 9.2. Venlafaxine was baseline resolved in its enantiomers using gamma-CD or HP-beta-CD, while imp1 (Wy45494) was baseline resolved using alpha-CD.