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Abstract
A simple, rapid and selective liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) is developed and validated for quantification of venlafaxine in human plasma with simple liquid-liquid extraction step consisted of extraction with ether and dichloromethane for 10 min and mixing with 1 M sodium acetate in human plasma using fluoxetine as an internal standard (IS). The analyte are separated using an isocratic mobile phase consisted of acetonitrile and 5 mM ammonium formate (4/3, v/v) on a isocratic YMC hydrosphere C18 (2.0x50.0 mm, 3.0 μm) column and analyzed by MS/MS in the multiple reaction monitoring (MRM) mode using the transitions of respective [M+H]+ ions, m/z 278.2→260.3 and m/z 310.1→148.1 for quantification of venlafaxine and IS, respectively. The standard calibration curves showed good linearity within the range of 1.0–200.0 ng/mL (r2=0.9986, 1/x2 weighting). The lower limit of quantification (LLOQ) was 1.0 ng/mL. The retention times of venlafaxine and IS were 0.6 min and 0.7 min that means the potential for the high-throughput potential of the proposed method. In addition, no significant metabolic compounds were found to interfere with the analysis. Acceptable precision and accuracy were obtained for the concentrations over the standard curve range. The validated method was successfully applied to bioequivalence study after 75-mg of venlafaxine sustained-release (SR) capsule in 24 healthy Korean subjects.
References
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Figure 1.
Chemical structures of (A) venlafaxine [(RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]-cyclohexanol, MW=277.402 g/ mol, C17H27NO2] and (B) fluoxetine [IS, (RS)-N-methyl-3-phenyl-3-[4-(trifluoromethyl) phenoxy] propan-1-amine, MW=309.33 g/mol, C17H18F3NO] (from ChemSpider free chemical data base).
Figure 2.
Chromatograms of (A) double blank plasma without venlafaxine and IS, (B) with IS (10.0 μg/mL), (C) with venlafaxine (LLOQ, 1.0 ng/mL) and IS (10.0 μg/mL), and (D) subject's plasma taken 10.0 h after a single oral dose of 75-mg venlafaxine capsule spiked with IS (10.0 μg/mL).
Figure 3.
Full-scan mass spectra of precursor (A, C) and product ions (B, D) of venlafaxine (m/z 278.2→260.4) and fluoxetine (m/z 310.2→148.1), respectively.
Figure 4.
Mean plasma concentrations versus time plots after a single oral dose of 75-mg venlafaxine SR capsule to the 24 healthy male subjects (○: reference, ●: test) (n=24, Mean±SD).
Table 1.
Method validation for the analysis of venlafaxine in human plasma and recovery of venlafaxine and IS (fluoxetine) after the extraction pro cedure, n=5
| Nominal Concentration (ng/mL) | Precision (%RSD)b | Accuracy (%) | ||
|---|---|---|---|---|
| Inter-day | Intra-day | Inter-day | Intra-day | |
| 1 (LLOQa) | 11.87 | 5.26 | 94.30 | 105.04 |
| 6 (low) | 5.04 | 5.03 | 102.39 | 101.02 |
| 100 (middle) | 4.38 | 2.55 | 101.94 | 106.27 |
| 160 (high) | 5.10 | 1.80 | 95.22 | 97.94 |
Table 2.
Pharmacokinetic parameters (mean±SD, n=24) of two formulations of 75-mg venlafaxine SR capsule based on its blood concentrations in the 24 healthy subjects
AUCt=area under plasma concentration-time curve from time 0 to t; AUC∞=area under plasma concentration-time curve from time 0 to infinite time; AUMCt=area under first moment of plasma concentration-time curve from time 0 to t; AUMC∞=area under first moment of plasma concentration-time curve from time 0 to infinite time; Vd=apparent volume of distribution; MRT=mean residence time; Cmax= peak plasma concentration; T1/2α=absorption half-life; Tmax=time for the Cmax; ka=absorption rate constant; T1/2α=elimination half-life; λz(ke) =elimination rate constant; CL=clearance.
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