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31 6 334 PDF
31, July/August2007
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High-Performance Liquid Chromatography-Tandem
Mass Spectrometry
Nad~ge Castaing, Karine Titier*, Mathilde Receveur-Daurel, Mait~ te-D~odic, Delphine te-bars,
Nicholas Moore, and Mathieu Molimard
Department of Clinical Pharmacologyand Toxicology, Pellegrin Hospital and University Victor Segalen,
33076 Bordeaux, France
Table I. MRM Transitions for the Detection of Antidepressants and Internal Standard (IS) by LC-MS-MS
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107,0 100
Desmethylmirtazapine 2,2 252.0 195.2 4.9 30 20 100
209.2 100
Mirtazapine 2.5 266,1 195.2 9.0 25 25 100
209.2 100
Milnacipran 3.1 247.1 230.3 2.5 15 15 100
100 100
Venlafaxine 3.8 278,1 260.3 1.5 20 10 100
121.1 100
I,S 7.8 422,0 201.2 - 35 35 100
Didesmethylcitalopram 7.9 297.0 109,0 1,8 25 20 100
262.2 100
Desmethylcitalopram 8.2 311.0 109.0 2.4 30 20 100
262.2 100
Citalopram 8.5 325,0 109,0 3.7 30 25 100
262,2 100
Fluvoxamine 10,6 319.0 258.2 1,7 20 10 100
200.2 100
Paroxetine 10.6 330,0 192.2 2.9 30 20 100
151,1 100
Noffluoxetine 12.0 296.0 134,1 6,7 15 6 100
30.0 100
Fluoxetine 12.4 310.0 148.1 0.2 15 8 100
43.9 100
Sertraline 12.8 306,0 159.0 0.9 15 25 100
275,1 100
s~150
12-08-~IRS- SAt4G-MedLeg.05 Sm (Mn, I ~ ) 2: MRM of 11 Cltanr,~ES+
12~064flE;- SAnG JdedLeg-05 3: MRM of 80lalm~sE S+ "r 422 ~ 201.2
" ~ 0 sefl~81~rle I~ 3 ~ 15~1121)4
. j ~ . . . . , . . . . , . . . . , . . . . , . . . . , . . . . , . . . . , . . 7.~. IS 7.39113
, . . . . . . . . . . . . . .
. . , . . . . , . . . . . . . . . , . . . . , . . . . . . . . . . . . . , . . . . , . . . . ,
j ~.
12-08-06-IRS- SAJ4G-NcdLeg-05Sm (Mn, 1]Q)
,0~ ,,o=, 2:MRM 0r 014ml~lES+
mnla~Une 1.Se~4
.,~
. .
8+00
12~&O6-1R5- S ~ e g
, .
~0.~
/~
.
I~/voxarnine
, . . . . , . . . .
10.~0
~ Sm (M~ 1~)
. . . . . . . . . . ,.
120~
. , . . , .
14.00 16.00
2: MRM 01"11OI~Ili~IsES+
+ , . .
3t9 ) 258.2
I 02e3
., ! 1 2 ~ R S - S ~
Ir
2.00
1~
-0SSm (Mn, I~Q)
deSIlltelh~WeftlaP4xPilil
4 0 0 6 0 0 a m
1: ~ MI0 ~
10.00
ES-,-
284,t >2,18.39,81e3
I~ Olalol~am 31259 lO9
. . . . , . . . . . . . . . . . . . . , . . . p , . . . . , . . . . . . . . . , . . . . , . . . . , . . . .
...... +,'+~ ....................................
,o| 12oo ,,| ,.~+~'"~ 2.00 4+~ 6.00 60D 10+00
12..Oe-OEARS- ~ -OGSm (Mn, I]Q) 2:MRM ofli Chemna~ES<. 12~S~64R~ ~ ~ S m (M~ lx2) 1: MRM of 10 ChaN)ds ES~
........ . . . . . . . . . . . . . . . . . . . . . '7.1+,=
8.00 t0fl0 1200 14.00 1600
12~RS- SA~G-MedLo~~ S m {M~ I]Q) 2:MRM o#11 C ~ E S +
.... , .... , , , . . . t , . . . . , . . . . , . . . . , . . . . , . . . .
'<'+I.
. . . , . . . .
~._ +,,,,,,,,.,,,~o,~
, .... , . . . . , . . . . , . . . . , . . . . + . . . . , . . . . , . . . .
~ i,,.+
=
, 12-06.,06JRS- SANG-.MedLeg..4D55m {Mn, 1x2)
2.00 4.00 6.00 800 10.00
1 MRM (11'10ChamPs ES+
8.0~ 10.~0 1200 14.00 1@00 / ~ 252 > 196.2
t2..08-~4P....%-S,A,NO-Ik~L~g,,,D5Sm (Mrl, 1~) ~: MRM 0;'11 Chann.l~SES+
~, 42'2 ~ 201 ?
iS 1.3Ge3
v--,- , ., .... ,. , ..-, .... ,..- , .,
B.00 1000 1200 14 00 1600 . . . . , . . . , . . . . , . . . . , . . . . , . . . . , .... , .... , .... , ....
200 4.~ 600 800 W.~
Time (mln)
Time (mln)
Figure 1. RepresentativeMRM chromatogramsof blood sample spiked Figure 2. RepresentativeMRM chromatogramsof blood sample spiked
with 50 ng/mLof each IRS.lhe transition of quantificationis shown for with 50 ng/mLof each other antidepressant. The transition of quantifi-
each compound. (I.S:internal standard.) cation is shown for each compound. (I.S: internal standard.)
335
Journal of Analytical Toxicology, Vol. 31, July/August 2007
(Saint Quentin Fallavier, France). Venlafaxine (V) and its Standard solutions
metabolite were a gift from Lederle (Pearl River, NY); citalo- The stock solutions w e r e prepared by dissolving accurately
pram, desmethylcitalopram, and didesmethylcitalopram were weighed a m o u n t in m e t h a n o l to yield a 1 m g / m L drug con-
from Lundbeck (Copenhagen, Denmark); mirtazapine and centration. A 1 m g / m L stock solution of internal standard in
desmethylmirtazapine were from Organon (Oss, The Nether- methanol was prepared and further diluted 1:1000 in methanol
lands); and milnacipran was from Pierre Fabre (Castres, to give a 1 IJg/mL w o r k i n g solution.
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France). Methylrisperidone, which was used as the internal Routine daily calibration curves and controls were prepared
standard (I.S.),was kindly donated by Lundbeck (Copenhagen, for each analytical batch in drug-free whole blood. Calibration
Denmark). standards were made to yield concentrations of 5, 10, 25, 50,
HPLC-grade solvents were purchased from Prolabo (Paris, 100, 250, and 500 ng/mL [20, 40, 100, 200, 400, 1000, and 2000
France), and analytical-grade chemicals were from Merck (No- ng/mL for V and desmethylvenlafaxine (DV)]. For the prepa-
gent sur Marne, France). ration of quality controls (QC) used for the validation of the
Drug-free blood from healthy volunteers was provided by assay, an independent stock solution was prepared and further
Etablissement FranCais du Sang (Bordeaux, France). diluted, to achieve concentrations of 10, 80, and 400 ng/mL
Intraday Interday
Added Observedconcentration Observed concentration
Compound Concentration
(ng/mL) (mean • SD, n = 4) CV (%) (mean • SD, n -- 15) CV (%) Bias (%)
336
Journal of Analytical Toxicology, Vol. 31, July/August 2007
Table III. Extraction and Matrix Effect Recoveries Data (40, 320, and 1600 ng/mL for V and DV).
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rations were performed at 25~ on a XTerra
Desmethylmirtazapine 80 69.9 • 2.3 3.0 98.0• 3.0 RP18 100- x 2.l-ram column (Waters). The
400 69.88 _+1.3 1.8 mobile phase consisted of a gradient of ace-
Desmethylvenlafaxine 320 53.00 + 1.8 3.4 84.4• 2.1 tonitrile/ammonium formate buffer (4
1600 58.1 • 4.3 mmol/L, pH 3.2). First, acetonitrile was set at
Mirtazapine 80 80.3 • 1.5 1.9 94.2• 1.1 15% (v/v) for 1 rain; then itwas increased lin-
400 77.8 • 5.7 7.3 early to 35% over 12 rain and set at 35% for 1
Milnacipran 80 19.9 • 6.4 3.2 96.4• 2.3 min. The system was then set at the initial
400 10.7 _+1.3 12.6 conditions in 30 s and was re-equilibrated over
I.S. 117.8• 6.5 101.8• 1.5
2.5 rain before the next injection. The total
Venlafaxine 320 85.4 • 1.9 2.3 102.0• 2.0
run time of the analysis was 17 min at a flow
1600 81.4 + 3.9 4.8
Didesmethylcitalopram 80 39.3 • 1.8 4.7 93.9• 5.1
rate of 0.3 mL/min.
400 31.5 • 2.3 7.2
Desmethylcitalopram 80 70.8 • 1.5 2.2 98.2• 1.0 MS
400 75.2 • 1.6 2.2 A QuattroMicro| triple quadrupole detector
Citaloprarn 80 81.5 • 2.3 2.8 100.4• 2.3 (Waters) with electrospray ionization (ESI) in
400 84.0_+7.1 8.5 positive ion mode was used for detection. The
Fluvoxamine 80 74.7 + 5.3 7.2 101,5• 3.3 MS was operated in the multiple-reaction
400 80.4 + 4.1 5.1 monitoring (MRM)mode.
Paroxetine 80 76.3 _+3.0 3.9 91.0• 4.2 The ESI source was operated at a tempera-
400 73.9 _+3.7 5.0
ture of 115~ The desolvation temperature
Noffluoxetine 80 70.7 + 3.1 4.3 104.0• 9.1
was set at 280~ The cone gas flow was set at
400 73.0 -+5.3 7.2
Fluoxetine 80 71.9 -+ 1.0 1.4 99.6• 3.5
50 L/h, and the desolvation gas flow was at
400 76.2 • 4.8 6.3 500 L/h. The capillary voltage was 3.2 kV.
Sertraline 80 73.4 • 1.0 1.3 99.6• 1.0 The cone voltages were optimized for each
400 74.6 -+7.3 9.7 compound. The MS collision gas was argon at
2.96 x 10-3 mbar, and the collision energies
blanc bllrN=
l ........
12-07-0C-IR.~- ~f'tr~ 00
*02 . . . . . . . ~ DO . . . . . . . d ~0 ....... 0 ~0 ..R
1 M . . .M. . or 101 0C' 0h0a n n" e"l s tZG+ i " " " " " " 8 D() " " " " . . . . . I O O O
" " '" " 1 1 ~ 2 i2003 '1 '1 4 0 0 ~ 1G:O0
-o . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .oo
T2-OT-O6-1R.~- e ~ e t - 0 2
......... .oo .oo ,ooo
1 M R M or 10 C t l a n n e l s E S +
4.gv3 264 1 > 246 3
9 5 1 0,4 3a , o1, r~#4 3 1 9 =~ ~ 3"6J5 4 ~ ~3u 03
~ 4 24 583 / 12-07-Or:3-lRg- ~ 1 - 0 2 2 ~M o f 11 C l ~ a n r ~ t s E S §
31 g 9 2 5 8 2
2 00 4.00 6 00 8 00 1Q.00 I~ 8 " W 7.315 205
12-07-0E,-IRS e f t e t - 0 2 1 M ~ M 0f 10 C h a n n e l s E S +
90 .17 252 > 195 2
IO0 7 40 O,~ 9 9.94 10.81.. , t2;0() . . . . 1.4;0()" 1e . o 0
. 163 204 3.74 f~?4
..... . ......... . .... , .... , .... , .... , .... . .... , .... , ....
2 O0 4.00 6 00 8.00 I 0 00 1;~.CI7.06-11R5- Ml'et . 0 2 2 h4~M o f 11 C n a n ~ e t i I~S,r
] 2 - 0 7 - 0 6 - 1 1 ~ - Eqte;-02 1 M R M or 10 C h a n n e l ~ E S + 9 2 5 9 109
~5 ?" 7,04 @ 1S 188
5 57 ~47 1 - 23O 3
a4 9 .229.51 0.70 10.~
. . . . . . . . , . . . . . . . . . . . . . . , . . . . . . . . . , . . . . , . . . . . . . . . . . . . .
-5
200 400 000 B00 1000 800 1000 " " "12'00 ....... 1"4:50 . . . . . . . 1~'.00
337
Ioumal of Analytical Toxicology, Vol, 31, luly/August 2007
were optimized for each compound. 0.5M). Seven milliliters of hexane/isoamylic alcohol (99:1, v/v)
Parent ions, the corresponding daughter ions, retention was added to the mixture, which was then shaken for 10 rain
times, cone voltages, collision energies, and dwell times opti- prior to being centrifuged at 5000 rpm for 10 rain. Then, 200
mized for each compound and the I.S. are presented in Table I. pL of HCI (0.05N) was added to the organic layer. The mixture
was further shaken for 10 min and centrifuged at 5000 rpm for
Sample preparation 10 min, following which 5 pL of the aqueous phase was in-
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Whole blood (500 pL) was spiked with 100 pL of internal jected into the HPLC unit.
standard (1 pg/mL) and 500 pL of carbonate buffer (pH 9.7,
Assay validation procedures
Itd 0
12,46.064RS- S,N'tG-MedL~g -02 3: MRM 0IS C~lnnelI E S~
Ion suppression. Ion suppression was investigated through
the addition of the analytes to blank matrix extracts. If the re-
................... >.'it
9
800 10C0 t20~ t400 1600 sponse of the analytes is compared to an unextracted standard
12.0~0~-~[~- SANG-Mc'~L6~ -02 3: MRM 018 (~16rln~li E ;Trr
solution at the same nominal concentration, any difference
8,00 1000 lZ~O 1400 18.00
from 100% recovery could be attributed to matrix effect. One
12-~II~ S,~NC~MeldLe9 -02 3: MRM o f ~ ChAnr~lI E S~
I
11~ 29G) 1~4 1 concentration (80 ng/mL or 320 ng/mL for V and DV) was an-
1144~ ~ 11~NI '~3.~4 3t75 14153.I/4"1615 7'2
V -,.. , ....
6.~
, ....
1000
.-- -.' "''~'"~':,"':',''':r
1200 14.00
'~: ,
16.0~
alyzed in replicates: three different human blood samples have
12~RS- S~G-MedLeg ~ 2 2: MRkl of 11 Cll14/l~dI E ~ -
been tested. To be acceptable, relative recoveries should be be-
7 1 7 -I . 31114~ 9{ ~i1141Q441 330 >
tween 80 and 120%. This acceptance criterion was recom-
800 1000 120Q 14.0~ 1600
12-O~B~IRS- SANG*I/4~L~ ~ 2
"~ 4 7 I e" ''A
2: MRM o f l l C I ~ I ~ I I E S +
3 1 9 > 2'S8 2
mended by the FDA Guidance (19).
.~j:_~'
r
~" A.'.~'~= "~ ~t,,~ .... , .... ,. ., .... ,
Linearity. A weighted least-squares quadratic regression
800 1000 IZ0,0 1400 16,00
12~-~RS- S/I~?~-MedlJ~ ~0~ 2: MRM 01'I I O h I V M l l E ~ * model for V and DV and a weighted least-squares linear re-
1 B I 9Jl
gression model for the others compounds were used to calcu-
12~6~1RS- S/~GJ~dlJ~ ~2
8.0# 10.(]0 1ZOO 14,~
2: MR u Ofll (~LMItl/I~IIE~
16.~
late the equation relating the peak-area ratio (drug vs. internal
77 2 . 8 ~ 311 9 1@9
standard) and the concentration of each compound in the cal-
124~0~-IR5-$ANG-MedLeQ-02 2: MRM 0 f l l C h a n ~ l s E S *
ibrators. The inverse of the concentration (l/x) was used as the
I 1 7.21
7
" 0,43 9 9.
10.74
10~
~7 > 10~
192 weighting factor. Three standard curves were analyzed.
800 1000 12~ 1400 1600
I2-Og~,EE~Iq,C~ ~A~4C=t;edt erl -~2 S m 0,I~ 1 ~ 2 M~M ~f ~ ' Chann~is~'S,
422 -201 2
1=00~ 7A7 IS lfe.~
s ~a~l~v~l;i;an~
v,-r .... ,- ,- ,- . -., .... ,. , ' , .... ,
800 1000 1200 1400 1600
Time (min)
std 0
12 03LI6 IRS S/4~G ~,!e'ILeg 02 S'r{,~tn, I~2; 2 MRhl ofll ChannesES+ I 7q ..--"
Figure 5. Representative MRM chromatograms of a zero sample (blank Figure6. Calibrationcurvesof venlafaxineevaluatedusinga weighted
human blood with the internal standard).The transitionof quantification least-squareslinear regressionmodel and a weighted least-squares
is shownforeachantidepressant. quadraticregressionmodel,
338
Journal of Analytical Toxicology, Vol. 31, )uly/August 2007
To determine the adequate fit linear model, the difference be- variation and bias lower than 20%.
tween the observed values and the fitted y-values expressed as Extraction recovery. Extraction recovery from human whole
coefficient of variation (CV) was examined for each standard blood was determined by comparing the response of extracts
concentration. The CV should be less than 15% for each plot of with the drug added before extraction against extracts with the
all calibration curves (19). drug added after extraction. Two quality control samples, con-
Precision. The precision of the developed method was de- taining 80 and 400 ng/mL of each compound (320 and 1600
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termined by analysis of three quality control samples con- ng/mL of V and DV),were analyzed four times.
taining 10, 80, and 400 ng/mL (40, 320, and 1600 ng/mL of V Specificity. The lack of interference from endogenous blood
and DV). Intraday variation of the assay was assessed by in- compounds was examined by analyzing different blank human
jecting four quality controls at each concentration on the same blood extracts with or without internal standard. Three dif-
day. Interday variation was assessed by injecting a further four ferent blank human blood samples from hospitalised patients
samples of each concentration on three subsequent days. Sub- were tested to check for the lack of interferences with each
sequently, the mean of each set of the concentrations, the drug and the internal standard.
standard deviation (SD), and coefficient of variation (CV)were The lack of interference from each drug and internal stan-
determined. The precision expressed as CVshould be less than dard to the MRM channels of the other drugs was checked by
15% for each QC sample (19). injecting pure solutions of each drug separately and searching
Bias. Biaswas measured as the percentage of difference from for the total absence of signal in the MRM channels of the
theoretical concentration according to the equation: other drugs.
~ 4.00
3.0~ g0
311 > 109
4,505e+O04
311 > 262.2
1.437e+~04
20~
1.0:l %
0.0D
O
l' r
i ........
;l~
Comgoundn~e: DesMe-Venlafa~ne
j lr l.i,..,=,,.r~
400
=l,
EGO
~eer.ie,.rlr
800
Time (min)
1000
r ~r e . e ~ l r
1~0
l,l,l,rl,l
14~0
e~r,, ii,
1~0
l,ir .,r~,
11~0
, i ....
-10
I I1~
III
.J I
I I
. , . . . . ,, . . , , . . -10 "'1,
CoeMctent OfDetefr~na~on:I~2 = 0.9~g234 7.50 10.00 7.50 1084
Calibra~0n r~ws -7.34183@007'x~2 + 0.00465345"x *-0,0111034
Resp onoe ~e: Ir~smalb~d ( Ref 6 ),/Yea * ( 18 Conc f IS Area ) Time (min) Time (min)
Curvetype:.~ndOrder.Ongin: Exclocle,Weighbng: ~/~s bins; None
DIDesMe-Citalopram DiDesMe-Citalopram
eooI .....---J"~ F2:MRM of 11 chanr'41s,E$+ F2:MRM of 11 c~annels, E$+
297 > 109 297 > 262.2.
Goo] / / / - / 6.154e+002 3.211 e+0O2
90 [OI 90"
!;i. ~, 10.50
.~ J ~j,'~__.._/-~
t~ 200 400 GOO 000 1000 1200 1400 1GO0 1800 -10 '"l ........ [' ' -t0
Time (rain) 7.50 10.0(] 7.50 10.50
Time (ndn) Time (min)
Figure 7. Calibration curves of desmethylvenlafaxineevaluated using a
weightedleast-squareslinearregressionmodeland a weightedleast- Figure 8. Chromatogram of a forensic peripheral blood with citalopram,
squares quadratic regression model. desmethylcitalopram, and didesmethylcitalopram.
339
Journal of Analytical Toxicology, Vol. 31, July/August 2007
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pounds were separated in 17 rain. and bias lower than 12% (Table II). The LOQ (5 ng/mL or 20
ng/mL for V and DV) and calibration range (5 to 500 ng/mL or
tinearity, precision, bias, and recovery 20 to 2000 ng/mL for V and DV)of the assay make our method
Calibration curves were linear in the range 5-500 ng/mL convenient for analysis of antidepressants in case of unknown
(20-2000 ng/mL for V and DV) (r2 > 0.995) with a slope varia- cause of death but also in cases of chemical abuse. Linearity
tion coefficient (n = 3) lower than 12%. was evaluated using a weighted least squares linear regres-
The results obtained for precision and bias are presented in sion model except for V and DV, a weighted least squares
Table II. The method showed intraday and interday precision, quadratic regression model was used. For these molecules,
expressed as CV, of less than 10%. A bias of less than 12% was both linear and quadratic regression models were evaluated.
achieved. The lower limit of quantification, determined as the However, the quadratic model provided a better fit in the range
lowest concentration of a given drug giving a response that 20-2000 ng/mL (Figures 6 and 7). The correlation coefficient
could be quantified with both interassay variation and bias r2 was always higher than 0.995. Furthermore, the CVfor each
lower than 20%, was 5 ng/mL (20 ng/mL for V and its metabo- plot of all calibration curves is less than 12%, and the low
lite). values were less underestimated.
The extraction recoveries obtained at the different tested In case of intoxication, concentrations higher than 500
concentrations are presented in Table III. The extraction re- ng/mL (2000 ng/mL for V and DV) could be found, and there-
coveries were between 70 and 90% except for desmethylmir- fore, samples must be diluted with blank whole blood. To val-
tazapine, DV, milnacipram, and didesmethylminalcipram. idate the dilution with blank matrix, a quality control sample
containing 1000 ng/mL (4000 ng/mL for Vand DV)was diluted
Specificity 1:10 in triplicates. The bias was lower than 15% (data not
As shown in Figure 3, no interference was seen from en- shown).
dogenous substances in drug-free human blood at the times of The present assay is used routinely in our laboratory. As an
interest. Figures 4 and 5 show the lack of interference from the example, we describe the case of a woman who was found dead
internal standard to the MRM channels of the drugs. in her residence by her husband. Deliberate self-poisoning was
suspected. First, a general drug screening by GC-MS and LC
Ion suppression with diode-array detection was carried out on the cardiac blood
The ion suppression assay did not show any significant re- and revealed the presence of olanzapine, alprazolam, zolpidem,
duction in the response of each drug. As shown in Table III, the citalopram, and viloxazine. No alcohol was detected. Therefore,
relative recoveries were more than 80%. No matrix effect was a quantitative analysis of citalopram and the other drugs was
observed. carried out on the peripheral blood. The concentrations were
6920 ng/mL for citalopram, 170 ng/mL for desmethylcitalo-
pram, and 18 ng/mL for didesmethylcitalopram. For citalo-
pram, the sample was diluted 1:20 (v/v) and analyzed again. The
Discussion chromatogram is shown in Figure 8.
340
Journal of Analytical Toxicology,Vol. 31, July/August2007
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