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Table 1 Applications of MSPD to the analysis of residues invarious matrices
Analyte(s) Matrix
Aminoglycosides Bovine kidneyBenzimidazoles Beef liverBenzimidazoles Swine muscleBeta-agonists Bovine liverCarbofuran CornChloramphenicol MilkChlorsulfuron MilkChlorsulon MilkClenbuterol Bovine liverFurazolidone Chicken muscleFurazolidone MilkFurazolidone Swine muscleIvermectin Fish muscleIvermectin MilkIvermectin Bovine liverMoxidectin Bovine tissuesNicarbazin Animal tissuesOxolinic acid CatfishOxytetracycline Catfish musclePCBs FishPesticides Beef fatPesticides Catfish musclePesticides CrayfishPesticides FishPesticides Fruit, vegetablesPesticides MilkPesticides OystersSulfa drugs Chicken tissuesSulfadimethoxine Catfish muscleSulfadimethoxine Catfish, plasmaSulfonamides Infant formulaSulfonamides MilkSulfonamides Salmon muscleSulfonamides Swine muscleSulfonamides EggsTetracyclines Milk
with such methods on several levels and should beconsidered as an alternative when pursuing new ana-lytical methodology. This is especially the case forsolid or semi-solid biological materials.
See also: II / Extraction: Solid-Phase Extraction; SolventBased Separation. III / Solid-Phase Extraction with Cart-ridges. Sorbent Selection for Solid-Phase Extraction.
Further Reading
Barker SA (1992) Application of matrix solid-phasedispersion (MSPD) to the extraction and subsequentanalysis of drug residues in animal tissues. In: AgarwalVK (ed.) Analysis of Antibiotic Residues in Food Prod-ucts of Animal Origin, pp. 119}132. New York: PlenumPress.
Barker SA and Floyd ZE (1996) Matrix solid-phase disper-sion (MSPD): implications for the design of newbonded-phase surface chemistries. In: Pesek JJ, MatyskaMT and AbuelaRya RR (eds) Chemically ModiTed Sur-faces: Recent Developments, pp. 66}71. Cambridge,UK: Royal Society of Chemistry.
Barker SA and Long AR (1992) Tissue drug residue extrac-tion and monitoring by matrix solid-phase dispersion(MSPD)-HPLC analysis. Journal of Liquid Chromatog-raphy 15: 2071}2089.
Barker SA, Long AR and Hines ME (1993) The disruptionand fractionation of biological materials by matrixsolid-phase dispersion. Journal of Chromatography629: 23}34.
Barker SA, Long AR and Short CR (1989) Isolation of drugresidues from tissues by solid-phase dispersion. Journalof Chromatography 475: 353}361.
Crouch MC and Barker SA (1997) Analysis of toxic wastesin tissues from aquatic species: applications of matrixsolid-phase dispersion. Journal of Chromatography 774:287}309.
US Patent � 5 272 094. Issued 21 December (1993)A bonded-phase matrix dispersion and extractionprocess. Isolation of drugs, and drug residues, frombiological specimens, and tissues (Dr Steven A Barker;co-patent applicant, Dr Austin R Long, Louisiana StateUniversity).
SOLID-PHASE MICROEXTRACTION
Biomedical Applications
H. Kataoka, Okayama University, Tsushima,Okayama, JapanH. L. Lord and J. Pawliszyn,University of Waterloo, Ontario, Canada
Copyright^ 2000 Academic Press
Analysis of drugs in biological samples is growing inimportance owing to the need to understand thetherapeutic and toxic effects of drugs and to continuethe development of more selective and effectivedrugs. Furthermore, the screening and conRrmationof abused drugs in body Suids is important for thedetection of potential users of drugs and the controlof drug addicts following withdrawal therapy. Simul-taneous analysis of these drugs in biological samples
III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications 4153
is required in many circumstances, such as clinicalcontrol for diagnosis and treatment of diseases, dop-ing control, forensic analysis and toxicology. Al-though high efRciency instruments have beendeveloped, most analytical instruments cannothandle the sample matrix directly. Therefore, samplepreparation is very important to achieve a practicaland reliable method for the analysis of complex ma-trices such as biological samples. In general, over80% of analysis time is spent on sampling and samplepreparation steps such as extraction, concentrationand isolation of analytes. However, previous samplepreparation techniques, such as liquid}liquid extrac-tion and solid-phase extraction, have their problems.These techniques are generally time-consuming andrequire large volumes of samples and solvents. Forexample, a long sample preparation time limits thenumber of samples that can be analysed, and multi-step procedures are prone to loss of analytes. Further-more, the use of a large amount of solvent inSuencestrace analysis, and also causes environmental pollutionand health concerns. Ideally, sample preparation tech-niques should be fast, easy to use, inexpensive andcompatible with a range of analytical instruments.
Solid-phase microextraction (SPME), developed byPawliszyn and co-workers in 1990, is a new samplepreparation technique using a fused-silica Rbre that iscoated on the outside with an appropriate stationaryphase. The analyte in the sample is directly extractedonto the Rbre coating. The method saves preparationtime, solvent purchase and disposal costs, and canimprove the detection limits. It has been used routine-ly in combination with gas chromatography (GC) andGC/mass spectrometry (GC/MS), and successfullyapplied to a wide variety of compounds, especially forthe extraction of volatile and semi-volatile organicpollutants from water samples. SPME was also intro-duced for direct coupling with high performanceliquid chromatography (HPLC) and LC/MS in orderto analyse weakly volatile or thermally labile com-pounds not amenable to GC or GC/MS. TheSPME/HPLC interface, equipped with a special de-sorption chamber, is utilized for solvent desorptionprior to HPLC analysis, instead of thermal desorptionin the injection port of the GC. Moreover, a newSPME/HPLC system known as in-tube SPME, wasrecently developed using an open-tubular fused-silicacapillary column as the SPME device in place ofthe SPME Rbre. In-tube SPME is suitable for automa-tion, and automated sample handling procedures notonly shorten the total analysis time, but also usuallyprovide better accuracy and precision relative tomanual techniques.
In this article, we review SPME techniquescoupled with various analytical instruments and the
applications of these techniques to drug analysis. Thereview consists of two main parts. In the Rrst part,general aspects of SPME techniques are surveyed forRbre and in-tube SPME methods coupled with vari-ous instruments. In the second part, applications ofthe SPME methods in drug analysis are consideredaccording to the drug type.
SPME Techniques Coupled withVarious Analytical Instruments
Fibre SPME
The Rbre SPME device consists of a Rbre holder andRbre assembly with built-in Rbre inside the needle. InRbre SPME, analytes are extracted directly from thesample onto a polymeric stationary phase coated onthe Rbre. When the Rbre is inserted into the sample,the target analytes partition from the sample matrixinto the stationary phase until equilibrium is reached.Two types of Rbre SPME techniques can be used toextract analytes: headspace SPME and immersionSPME. In headspace SPME, the Rbre is exposed in theheadspace of gaseous, liquid or solid samples. Inimmersion SPME, the Rbre is directly immersed inliquid samples. The Rbre with concentrated analytesis then transferred to an instrument for desorption,followed by separation and quantiRcation. Head-space and immersion SPME techniques can be used incombination with any GC, GC/MS, HPLC andLC/MS system. The process of the Rbre SPME/GCmethod is shown in Figure 1.
In Rbre SPME, the amount of analyte extractedonto the Rbre depends on the polarity and thicknessof the stationary phase coating on the Rbre, extrac-tion time, and the concentration of analyte ina sample. In general, volatile compounds requirea thick polymer coat and a thin coat is effective forsemi-volatile compounds. Extraction of analytes isalso typically improved by agitation, addition of saltto the sample, changing the pH, and temperature.Although full equilibration is not necessary for accu-rate and precise analysis by SPME, consistent extrac-tion time and other SPME parameters are essential.Furthermore, it is important to keep a consistent vialsize and sample volume. In general, immersion SPMEis more sensitive than headspace SPME for analytespredominantly present in the liquid. On the otherhand, headspace SPME is suitable for the extractionof more volatile compounds. Extractions from biolo-gical samples by headspace SPME exhibit lower back-ground than extractions obtained by immersionSPME. Because the headspace and immersion SPMEtechniques differ in kinetics, both approaches shouldbe evaluated to optimize Rbre SPME conditions for
4154 III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications
Figure 1 Schematic illustration of headspace and immersion SPME/GC methods. (A) Headspace SPME; (B) direct immersionSPME.
analytes. Fibre SPME techiques in combination withGC or GC/MS are unsuitable for the extraction of lessvolatile or thermally labile compounds. Thus derivat-ization approaches are frequently used to extract po-lar compounds from biological samples. Four types ofderivatization techniques in combination with SPMEare implemented. Direct derivatization in the samplematrix is similar to well-established approaches usedin solvent extraction. Analytes are extracted by SPMEafter derivatization in the vial. For in-coating derivat-ization with the Rbre-doping method, simultaneousderivatization and extraction are directly performedin the Rbre coating by a two-step process: (1) dopeRbre with derivatization agent and (2) expose doped
Rbre to sample for extraction. This technique can beused for polar volatile compounds. Another in-coat-ing derivatization technique is performed by the fol-lowing two-step process: (1) dope Rbre to sample forextraction and (2) expose doped Rbre in the head-space of derivatizing agent. For derivatization in theinjection port, the analyte extracted by SPME is de-sorbed in a GC injection port and then derivatizedwith additional reagent.
The desorption of analyte from the Rbre coating isperformed by heating the Rbre in the injection port ofa GC or GC/MS, or by loading solvent into thedesorption chamber of the SPME/HPLC interface.EfRcient thermal desorption of an analyte in a GC
III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications 4155
Figure 2 Schematic of the SPME-HPLC system. (a) Stainless steel (SS) 1/16 inch tee joint; (b) 1/16 inch o.d., 0.02 inch i.d., SStubing; (c) 1/16 inch o.d. poly(ether ether ketone) (PEEK) tubing (0.02 inch i.d.); (d) two-piece finger-tight PEEK union; (e) PEEKtubing (0.005 inch i.d.) with a one-piece PEEK union. (Reproduced with permission from Pawliszyn J (1997) Solid Phase Microextrac-tion: Theory and Practice. Translated by permission of John Wiley & Sons, Inc. All rights reserved.)
injection port is dependent on the injection depth,injector temperature, and exposure time. A narrow-bore GC injector insert is required to ensure highlinear Sow and the Rbre needs to be exposed immedi-ately after the needle is introduced into the insert.Needle exposure depth should be adjusted to placethe Rbre in the centre of the hot injector zone. Desorp-tion time is determined by the injector temperatureand the linear Sow rate around the Rbre. The HPLCinterface, on the other hand, consists of a six-portinjection valve and a special desorption chamber, andrequires solvent desorption of the analyte prior toHPLC or LC/MS analysis. A typical SPME/HPLCinterface is shown in Figure 2. The desorption cham-ber is placed in the position of the injection loop.After sample extraction, the Rbre is inserted into thedesorption chamber at the ‘load’ position under am-bient pressure. When the injector is changed to the‘inject’ position, mobile phase contacts the Rbre, de-sorbs the analytes, and delivers them to the HPLCcolumn for separation. Two desorption techniquescan be used to remove the analytes from the Rbre:dynamic desorption and static desorption. In dy-namic desorption, the analytes can be removed bya moving stream of mobile phase. When the analytes
are more strongly adsorbed to the Rbre, the Rbre canbe soaked in mobile phase or other strong solvent fora speciRed time by static desorption before injectiononto the HPLC column. In each desorption tech-nique, rapid and complete desorption of analytes us-ing minimal solvent is important for optimizing theSPME/HPLC or SPME/LC/MS methods.
In-tube SPME
In-tube SPME using an open-tubular capillary col-umn as the SPME device was developed for couplingwith HPLC or LC/MS. It is suitable for automation,and can continuously perform extraction, desorptionand injection using a standard autosampler. With thein-tube SPME technique, organic compounds inaqueous samples are directly extracted from thesample into the internally coated stationary phase ofa capillary column, and then desorbed by introducinga moving stream of mobile phase or static desorptionsolvent when the analytes are more strongly absorbedto the capillary coating. A schematic diagram of theautomated in-tube SPME/LC/MS system is shown inFigure 3. The capillaries selected have coatingssimilar to those of commercially available SPMERbres. The capillary column is placed between the
4156 III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications
Figure 3 Schematic of the in-tube SPME/LC/MS system. (A) Load position (extraction phase); (B) injection position (desorptionphase). (Reproduced with permission from Kataoka H, Narimatsu S, Lord HL and Pawliszyn J (1999) Analytical Chemistry 71: 4237.Copyright American Chemical Society.)
injection loop and the injection needle of the HPLCautosampler. While the injection syringe repeatedlydraws and ejects sample from the vial under com-puter control, the analytes partition from the samplematrix into the stationary phase until equilibrium isreached. Subsequently, the extracted analytes are dir-ectly desorbed from the capillary coating by mobilephase Sow or by aspirating a desorption solvent. Thedesorbed analytes are transported to the HPLC col-umn for separation, and then detected with UV ora mass selective detector (MSD).
In in-tube SPME, the amount of analyte extractedby the stationary phase of the capillary column de-pends on the polarity of capillary coating, numberand volume of draw/eject cycles and the sample pH.A capillary column 50}60 cm long is optimal forextraction. Below this level, extraction efRciency isreduced, and above this level, peak broadening isobserved. In general, complete equilibrium extractionis not obtained for any of the analytes, because theanalytes are partially desorbed into the mobile phase
during each eject step. The target analytes with higherK-values need longer equilibration times. Althoughan increase in number and volume of draw/ejectcycles can enhance the extraction efRciency, peakbroadening is often observed in this case. The optimalSow rate of draw/eject cycles is 50}100 �L min�1.Below this level, extraction requires an inconvenient-ly long time, and above this level, bubbles form on theinside of the capillary and extraction efRciency isreduced. The in-tube SPME technique does not needa special SPME/HPLC interface for desorption ofanalytes. The analytes extracted onto the capillarycoating can be easily desorbed by a moving stream ofmobile phase or desorption solvent when the analytesare more strongly adsorbed to the capillary coating.Carryover in the in-tube SPME method is lower oreliminated in comparison with the Rbre-SPMEmethod.
Although the theories of Rbre and in-tube SPMEmethods are similar, the signiRcant difference be-tween these methods is that the extraction of analytes
III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications 4157
is performed on the outer surface of the Rbre forRbre-SPME and on the inner surface of the capillarycolumn for in-tube SPME. Therefore, with the in-tubeSPME method, it is necessary to prevent plugging ofthe capillary column and Sow lines during extraction,and typically particles must be removed from samplesby Rltration before extraction. On the other hand,with the Rbre-SPME method, it is not necessary toremove particles before extraction because they areremoved by washing the Rbre with water before inser-tion into the desorption chamber of the SPME/HPLCinterface. Another signiRcant difference between in-tube SPME and manual Rbre-SPME/HPLC is the pos-sible decoupling of desorption and injection with thein-tube SPME method. In the Rbre-SPME method,analytes are desorbed during injection as the mobilephase passes over the Rbre. On the other hand, in thein-tube SPME method, analytes are desorbed by mo-bile phase or by aspirating a desorption solvent froma second vial, and then transferred to the HPLCcolumn by mobile-phase Sow. The Rbre-SPME/HPLC method also has the advantage of eliminat-ing the solvent peak from the chromatogram, butpeak broadening is sometimes observed becauseanalytes can be slow to desorb from the Rbre. Withthe in-tube SPME method, peak broadening is notobserved because analytes are completely desorbedbefore injection.
Biomedical Applications: DrugAnalysis
SPME methods applied to the analysis of variousabused and therapeutic drugs in biological samplesare listed in Table 1, according to the drug type,sample type, extraction device, extraction mode, andanalytical technique. The SPME methods using 100-�m polydimethylsiloxane (PDMS) Rbres in combina-tion with GC or GC/MS are widely used for theanalysis of various drugs. The SPME methodscoupled with HPLC or LC/MS are used for the analy-sis of less volatile or thermally labile drugs. For recentreviews of some of these methods for drug analysissee Pawliszyn, Lord and Pawliszyn, Namera et al.,Junting et al., Kataoka et al. and Sporkert and Pragstin the Further Reading section.
Amphetamines and Related Compounds
Yashiki and co-workers developed a simple and rapidmethod for analysing amphetamine (AM) and meth-amphetamine (MA) in urine and blood samples byheadspace SPME and GC/MS-selected ion monitor-ing (SIM). In order to move the analytes into theheadspace, the sample was heated at 803C for 20 minunder K2CO3 or NaOH alkaline conditions. Sub-
sequently, a 100-�m PDMS Rbre was exposed to theheadspace for 5 min, and then inserted into the injec-tion port of GC/MS for desorption. The method wastwenty times more sensitive than the conventionalheadspace method. Lord and Pawliszyn optimizedseveral extraction parameters for the analysis of AMand MA in urine samples by headspace SPME/GC-Same ionization detection (FID). Centini et al.and Battu et al. reported simultaneous analysisof amphetamines and their analogues, such as3,4-methylenedioxyamphetamine (MDA), 3,4-methyl-enedioxymethamphetamine (MDMA) and 3,4-methy-lenedioxyethylamphetamine (MDEA), in urine sam-ples by headspace SPME using a 100-�m PDMS Rbre.As shown in Figure 4, a clean total-ion chromatogramis obtained from a urine sample spiked with100 ng mL�1 of each of the 21 central nervous systemstimulants and extracted by the headspace SPMEmethod. Koide et al. applied this technique to theanalysis of amphetamines in hair samples.
Degel, Penton, Ishii et al., Makino et al. andMyung et al. used the direct immersion technique inorder to improve the extraction efRciency and sensi-tivity. The extraction recoveries of AM and MA bythe immersion SPME method are several times higherthan those by the headspace SPME method. Ugland etal. reported an SPME technique in combination withderivatization. After derivatization with alkylchloro-formate, amphetamines and their methylenedioxyanalogues were analysed by immersion-Rbre SPME/GC-nitrogen-phosphorus detection (NPD) or GC/MS.
Kataoka et al. developed an in-tube SPME/LC/MSmethod for the analysis of amphetamines and theirmethylenedioxy analogues using Omegawax (Supelco,Bellefonte, PA, USA) capillary as the extractiondevice. As shown in Figure 5, these drugs spiked intourine samples were selectively analysed without inter-ference peaks by SIM-mode detection.
Anaesthetics
Kumazawa et al. developed headspace and direct-immersion-SPME methods for the analysis of ten lo-cal anaesthetics in blood samples. These drugs wereextracted with 100-�m PDMS Rbres after deprotein-ization of the sample with perchloric acid. Heating ina NaOH and (NH4)2SO4 solution during headspaceSPME gave the best recoveries of the drugs and thecleanest backgrounds. The recoveries for all drugs inthe sample mixture at neutral pH in the presence ofNaCl were greater than for that of a sample at thesame pH without NaCl (see Figure 6). Althougha small amount of background noise appeared in thedirect immersion-SPME method, the advantage ofusing immersion-SPME is that recovery is much bet-ter than that of headspace-SPME.
4158 III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications
Table
1S
PM
Em
etho
dsfo
rth
ean
alys
isof
drug
sin
biol
ogic
alsa
mpl
es
Dru
gsS
peci
men
Ext
ract
ion
devi
ceE
xtra
ctio
nm
odea
Hyp
hena
ted
anal
ysis
Ref
eren
ce
Am
phet
amin
esan
dre
late
dco
mpo
unds
AM
,M
AU
rine
100-
�mP
DM
Sfib
reH
SG
C/M
SF
oren
sic
Sci
.In
t.(1
995)
76:
169.
AM
,M
AB
lood
100-
�mP
DM
Sfib
reH
SG
C/M
SF
oren
sic
Sci
.In
t.(1
996)
78:
95.
AM
,M
A,
MD
MA
,M
DE
AU
rine
100-
�mP
DM
Sfib
reH
SG
C/M
SF
oren
sic
Sci
.In
t.(1
996)
83:
161.
AM
,M
AU
rine
100-
�mP
DM
Sfib
reD
IG
C/M
SC
lin.
Bio
chem
.(1
996)
29:
529.
AM
,M
AU
rine
100-
�mP
DM
Sfib
reD
IG
C/F
IDC
an.
Soc
.F
oren
sic
Sci
.J.
(199
6)29
:43
.A
M,
MA
Urin
e65
-�m
PD
MS/D
VB
fibre
DI
GC
/NP
DJp
n.J.
For
ensi
cT
oxic
ol.
(199
6)14
:22
8.A
M,
MA
Urin
e10
0-�m
PD
MS
fibre
HS
GC
/FID
Ana
l.C
hem
.(1
997)
69:
3899
.A
M,
MA
Urin
e10
0-�m
PD
MS
fibre
D#
DI
GC
/NP
DJ.
Chr
omat
ogr.
B(1
997)
701:
29.
GC
/MS
MA
Urin
e10
0-�m
PD
MS
fibre
DI
GC
/NP
DC
hrom
atog
raph
y(1
997)
18:
185.
GC
/MS
AM
,M
A,
MD
A,
MD
MA
,M
DE
Aet
c.U
rine
100-
�mP
DM
Sfib
reH
SG
C/M
SJ.
Chr
omat
ogr.
Sci
.(1
998)
36:
1.A
M,
MA
Hai
r10
0-�m
PD
MS
fibre
HS
GC
/NP
DJ.
Chr
omat
ogr.
B(1
998)
707:
99.
AM
,M
A,
MD
MA
Urin
e10
0-�m
PD
MS
fibre
DI
GC
/MS
J.C
hrom
atog
r.B
(199
8)71
6:35
9.A
M,
MA
,M
DA
,M
DM
A,
MD
EA
Urin
e10
0-�m
PD
MS
fibre
D#
DI
GC
/NP
DJ.
Pha
rm.
Bio
med
.A
nal.
(199
9)19
:46
3.G
C/M
SA
M,
MA
,M
DA
,M
DM
A,
MD
EA
Urin
eO
meg
awax
250
capi
llary
ITLC
/MS
J.C
hrom
atog
r.B
(sub
mitt
ed).
J.A
nal.
Tox
icol
.(2
000)
24:
inpr
ess.
Ana
esth
etic
sLi
doca
ine
etc.
Blo
od10
0-�m
PD
MS
fibre
HS
GC
/FID
Jpn.
J.F
oren
sic
Tox
icol
.(1
995)
13:
182.
Lido
cain
eet
c.B
lood
100-
�mP
DM
Sfib
reD
IG
C/F
IDC
hrom
atog
raph
ia(1
996)
43:
59.
Phe
ncyc
lidin
eU
rine,
bloo
d10
0-�m
PD
MS
fibre
HS
GC
/SID
Chr
omat
ogra
phia
(199
6)43
:33
1.Li
doca
ine
etc.
Blo
od10
0-�m
PD
MS
fibre
HS
GC
/MS
J.C
hrom
atog
r.B
(199
8)70
9:22
5.G
C/F
IDC
hrom
atog
raph
ia(1
998)
47:
678.
Lido
cain
eU
rine
100-
�mP
DM
Sfib
reD
IH
PLC
/UV
Ano
rect
ics
Fen
flura
min
eU
rine
30-�
mP
DM
Sfib
reD
IG
C/M
SJ.
Mic
roco
lum
nS
ep.
(199
7)9:
249.
Ant
idep
ress
ants
Am
itrip
tylin
e,im
ipra
min
eet
c.U
rine
100-
�mP
DM
Sfib
reH
SG
C/F
IDJp
n.J.
For
ensi
cT
oxic
ol.
(199
5)13
:25
.A
mitr
ipty
line
Urin
e10
0-�m
PD
MS
fibre
DI
GC
/MS
Clin
.B
ioch
em.
(199
6)29
:52
9.A
mitr
ipty
line,
imip
ram
ine
etc.
Pla
sma
100-
�mP
DM
Sfib
reD
IG
C/N
PD
J.C
hrom
atog
r.B
(199
7)69
6:21
7.A
mitr
ipty
line,
imip
ram
ine
etc.
Blo
od10
0-�m
PD
MS
fibre
HS
GC
/FID
J.C
hrom
atog
r.S
ci.
(199
7)35
:30
2.M
apro
tilin
e,m
ians
elin
e,se
liptil
ine
Blo
od10
0-�m
PD
MS
fibre
HS
GC
/MS
J.A
nal.
Tox
icol
.(1
998)
22:
396.
Ant
iepi
lept
ics
Val
proi
cac
idP
lasm
a10
0-�m
PD
MS
fibre
DI
GC
/FID
J.C
hrom
atog
r.B
(199
5)67
3:29
9.
III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications 4159
Table
1C
ontin
ued
Dru
gsS
peci
men
Ext
ract
ion
devi
ceE
xtra
ctio
nm
odea
Hyp
hena
ted
anal
ysis
Ref
eren
ce
Ant
ihis
tam
inic
sD
iphe
nhyd
ram
ine
etc.
Urin
e,bl
ood
100-
�mP
DM
Sfib
reH
SG
C/F
IDJ.
Chr
omat
ogr.
Sci
.(1
997)
35:
275.
Ran
itidi
neU
rine
Om
egaw
ax25
0ca
pilla
ryIT
LC/M
SJ.
Chr
omat
ogr.
B(1
999)
731:
353.
Ant
ihyp
erte
nsiv
esP
ropr
anol
olet
c.U
rine,
seru
mO
meg
awax
250
capi
llary
ITLC
/MS
Ana
l.C
hem
.(1
999)
71:
4237
.
Ant
ipsy
chot
ics
Pro
maz
ine
etc.
Urin
e,bl
ood
100-
�mP
DM
Sfib
reH
SG
C/F
IDJp
n.J.
For
ensi
cT
oxic
ol.
(199
6)14
:30
.
Bar
bitu
rate
sB
arbi
tale
tc.
Urin
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4160 III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications
Figure 4 Total-ion chromatogram of a urine sample extract spiked with 21 central nervous system stimulants at 1000 �g L�1. SPMEconditions: fibre, 100 �m PDMS; extraction, at 803C headspace for 10 min with stirring; desorption, exposure for 10 min in GC injectionport. GC/MS conditions: column, PTA-5 (30 m�0.32 mm i.d., 0.5 �m film thickness); injector, splitless mode at 2003C; split openingtime, 2 min; oven temperature, programme from 60 to 1203C at 303Cmin�1, then to 2103C at 53C min�1, and finally to 2803C at303C min�1 and hold at 2803C for 5 min; transfer line and detector temperature, 2803C; helium flow-rate, 1.3 mL min �1, ionization,70 eV. (Reproduced with permission from Battu C, Marquet P, Fauconnet AL, Lacassie E and Lacha( tre G (1998) Journal ofChromatographic Science 36: 1, by permission of Preston Publications, A Division of Preston Industries, Inc.)
Furthermore, Kumazawa et al. reported a methodfor analysis of phencyclidine in urine and wholeblood by headspace-SPME and GC with a surfaceionization detector (SID). Watanabe et al. developeda simple method for analysis of Rve local anaestheticsin blood samples by headspace SPME using a 100-�mPDMS Rbre and GC/MS-SIM. Koster et al. reporteddirect immersion-SPME methods coupled with GC-FID and HPLC-UV for the determination of lidocainein urine samples. Desorption of the PDMS Rbre inHPLC is more complicated than the desorption inGC, because it is dependent on the composition of themobile phase or the desorption solvent.
Antidepressants
Kumazawa et al. developed a simple headspace-SPME method for the analysis of four tricyclic antide-pressants in urine and whole-blood samples. Thesedrugs were extracted with a 100-�m PDMS Rbre afterheating at 1003C in the presence of a NaOH solution.Namera et al. reported a headspace-SPME/GC-MSmethod for the analysis of three tetracyclic antide-pressants in whole-blood samples, and its applicationto a medicolegal case of setiptiline intoxication.Ulrich and Martens developed a direct immersion-SPME method for the simultaneous analysis of tenantidepressant drugs and metabolites in plasma sam-
ples, and applied the method to toxicological analysisafter the accidental or suicidal intake of higher doses.The sample was extracted with a 100-�m PDMS Rbrefor 10 min and the Rbre was exposed in the GCinjection port at 2603C for 1 min after washing in50% methanol and subsequent drying at room tem-perature. As shown in Figure 7, these drugs in plasmasamples were selectively analysed by NPD withoutinterference peaks. However, the recoveries of antide-pressants from plasma samples were very low due tothe high protein binding of these drugs. The limits ofquantiRcation for these drugs in plasma samples were90}200 ng mL�1. The sensitivity can be considerablyimproved by increasing the extraction time and dilu-tion of plasma samples with water.
Benzodiazepines
Krogh et al. developed a direct immersion-SPMEmethod in combination with GC-NPD for the analy-sis of diazepam in plasma samples. The polyacrylate(PA) Rbre doped with 1-octanol was used to extractdiazepam from the samples. The solvent-modiRed PARbre was found to be more efRcient in the extractionof diazepam than the untreated PA and PDMS Rbres.This technique offers sufRcient enrichment forbioanalysis, high selectivity, and short samplepreparation time. However, the potential of the
III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications 4161
Figure 5 Total ion and SIM chromatograms obtained from urine samples spiked with amphetamines by in-tube SPME/LC/MS.(A) Total ion chromatograms obtained from urine and spiked urine samples; (B) SIM chromatograms obtained from spiked urinesample. Urine sample (10 �L) was diluted ten times with water and used for analysis after filtration. Stimulants were spiked ata concentration of 5 mg mL�1 urine. LC/MS conditions: column, Supelcosil LC-CN (3.3 cm�4.6 mm i.d., 3 �m particle size); columntemperature, 253C; mobile phase, acetonitrile/50 mM ammonium acetate (15 : 85); flow-rate, 0.4 mL min�1; fragmentor voltage, 40 V;ionization mode, positive ESI; SIM ion, m/z"136 (AM), 150 (MA), 180 (MDA), 194 (MDMA) and 208 (MDEA). In-tube SPMEconditions: capillary, Omegawax 250 (60 cm�0.25 mm i.d., 0.25 �m film thickness); sample pH, 8.5; draw/eject cycles, 15; draw/ejectvolume, 35 �L; draw/eject flow-rate, 100 �L min�1, desorption solvent, mobile phase. Peaks: 1, AM; 2, MDA; 3, MA; 4, MDMA; and 5,MDEA. (Reproduced with permission from Kataoka H, Lord HL and Pawliszyn J (2000) Journal of Analytical Toxicology 24: 263, bypermission of Preston Publications, A Division of Preston Industries, Inc.)
solvent-modiRed SPME technique is limited by theincompatibility of the SPME coatings with most or-ganic solvents. Luo et al. developed a direct immer-sion-SPME method for the simultaneous analysis of
Rve benzodiazepines in urine and serum samples.These drugs were efRciently extracted from thesesamples with a 65-�m Carbowax/divinylbenzene(DVB) Rbre under conditions of saturated salt with
4162 III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications
Figure 6 Capillary GC of ten local anaesthetics extracted from human whole blood by use of direct immersion-SPME. (A) Theauthentic drugs (50 ng each on column); (B) a drug extract at pH 7 without salt; (C) a drug extract at pH 7 in the presence of 0.5 g NaCl;(D) a blank extract at pH 7 in the presence of 0.5 g NaCl. The mixture of ten drugs (5 �g each) was added to 1 mL of human whole blood.SPME conditions: fibre, 100 �m PDMS; extraction, at room temperature for 40 min with stirring; desorption, 1 min exposure in GCinjection port. GC conditions: column, DB-17 (30 m�0.25 mm i.d., 0.25 �m film thickness); column temperature, initially hold at 1003Cfor 1 min and increase to 2903C at 103Cmin�1; injector and detector temperatures, 2503C; He carrier gas flow-rate, 3 mL min�1;injection, splitless; detector, FID. Peaks: 1, ethyl aminobenzoate; 2, prilocaine; 3, lidocaine; 4, procaine; 5, mepivacaine; 6, tetracaine;7, bupivacaine; 8, p-(butylamino)benzoic acid-2-(diethylamino)ethyl ester; 9, benoximate; and 10, dibucaine. (Reproduced withpermission from Kumazawa T, Sato K, Seno H, Ishii A and Suzuki O (1996) Chromatographia 43: 59.)
pH 7 and sampling at 453C with agitation, and ana-lysed by GC-MS.
Guan et al. analysed the metabolites of benzo-diazepines from acid-hydrolysed urine samples usinga direct immersion-SPME method in combinationwith GC-electron capture detection (ECD). The de-tection limits were 2}20 ng mL�1 for most drugs tes-ted. Jinno and Taniguchi, however, developed anSPME method coupled with HPLC for the analysis ofsix benzodiazepines in human urine samples. Sensitiv-
ity may be increased by the combination of saturatedsalt and weakly alkaline conditions in the extractionmatrix. As shown in Figure 8, a 65-�m PA Rbre wasfound to be more efRcient in the extraction of ben-zodiazepines than a 100-�m PDMS Rbre.
Narcotics and Other Illicit Drugs
Kumazawa et al. and Makino et al. developed directimmersion SPME methods in combination withGC-NPD for the rapid analysis of cocaine in urine
III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications 4163
Figure 7 Typical SPME-GLC-NPD chromatograms obtained from (A) blank plasma with internal standard, (B) plasma spiked withten antidepressant drugs and metabolites, each 375 ng mL�1, and (C) a sample of a patient after suicidal intoxication with amitriptyline(amitriptyline, 766 ng mL �1; nortriptyline, 489 ng mL�1. SPME conditions: fibre, 100-�m PDMS; extraction, shaking at 700 rpm for10 min at 223C; desorption, 1 min exposure in GC injection port. GC conditions: column, DB-1 (30 m�0.32 mm i.d., 0.25 �m filmthickness); column temperature, programme from 1403C to 2203C at 203Cmin�1 and from 2203C to 2703C at 23C min�1; injector anddetector temperatures, 2603C and 3003C, respectively; N2 carrier gas flow-rate, 0.7 mL min�1; injection, splitless; detector, NPD.Peaks: 1, amitriptyline; 2, trimipramine; 3, imipramine; 4a, cis-doxepine; 4b, trans-doxepine; 5, nortriptyline; 6, mianserine; 7,desipramine; 8, maprotiline; 9, clomipramine; and 10, desmethylclomipramine. IS, internal standard (chloramitriptyline). (Reproducedwith permission from Ulrich S and Martens J (1997) Journal of Chromatography B 696: 217. Copyright Elsevier Science.)
4164 III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications
Figure 8 Chromatograms of extracted drugs with (A) 100-�m PDMS and (B) 85-�m PA. SPME conditions: extraction, stirring at840 rpm for 3 h at 603C; desorption, 30 min exposure in desorption chamber. HPLC conditions: column, Siperiorex ODS(250 mm�1.5 mm i.d.); mobile phase, acetonitrile/water; flow-rate, 100 �L min�1; detection, UV at 220 nm. Peaks: 1, nitrazepam; 2,flunitrazepam; 3, fludiazepam; 4, diazepam; 5, clotiazepam; and 6, medazepam. (Reproduced with permission from Jinno K andTaniguchi M (1997) Chromatography 18: 244.)
samples. Recovery of cocaine by this techniqueusing a 100-�m PDMS Rbre was 20%, and thedetection limit was about 12 ng mL�1. Lordand Pawliszyn applied the SPME/GC-FID methoddeveloped for amphetamines to the analysis ofmeperidine, codeine, methadone, morphine and her-oin in spiked urine samples. Furthermore, Hall et al.applied an immersion SPME technique to the analysisof four cannabinoids in human saliva. These drugswere extracted with a 100-�m PDMS Rbre and ana-lysed in the range from 5 to 500 ng mL�1 by GC/MS.Using this method, �9-tetrahydrocannabinol (�9-THA) was detected in a saliva sample collected30 min after the subject had smoked marijuana(Figure 9).
Strano-Rossi and Chiarotti reported an immers-ion SPME method using a 30-�m PDMS Rbre incombination with GC/MS for the analysis of canna-binoids in alkaline hydrolysed hair samples. Themethod is also applied to the analysis of other drugssuch as methadone, cocaine and cocaethylene in hairsamples.
Other Drugs
Yashiki et al. developed a simple and rapid methodfor the analysis of nicotine and its principal metab-olite, cotinine, in urine samples using headspaceSPME and GC/MS-SIM. Krogh et al. applied a directimmersion SPME technique to the analysis of theantiepileptic drug valproic acid in plasma samples.The drug was extracted with a 100-�m PDMS Rbreafter dialysis of plasma samples, and then analysed byGC-FID. Seno et al. developed headspace SPMEmethods for the simple analysis of Rve phenothiazinedrugs and thirteen diphenylmethane antihistaminicdrugs and their analogues in urine and whole bloodsamples. A 100-�m PDMS Rbre was exposed in theheadspace of the sample vial after preheating of thesample in the presence of NaOH, and the drugs extrac-ted in the Rbre were analysed by GC-FID. The recove-ries from blood extracts were lower than those fromurine extracts for all drugs. Hall and Brodbelt reporteda direct immersion SPME method coupled with ion-trap GC/MS for the analysis of eight barbiturates in
III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications 4165
Figure 9 Chromatograms after performing SPME on human saliva samples prior to and after marijuana smoking. (A) SIMchromatogram of saliva sample before marijuana smoking; (B) total ion chromatogram of saliva sample after marijuana smoking;(C) SIM chromatogram of saliva sample after marijuana smoking. SPME conditions: fibre, 100 �m PDMS; extraction, immersion for10 min with stirring; desorption, exposure for 12 min in GC injection port. GC/MS conditions: column, DB-5ms (30 m�0.25 mm i.d.,0.5 �m film thickness); oven temperature, initially hold at 503C for 0.2 min and increase to 2803C at 153Cmin�1, and finally hold at2803C for 2 min; transfer line temperature, 2803C; detection, ion trap (electron ionization mode); SIM ion, �9 -THC (m/z"231, 299,314). (Reproduced with permission from Hall BJ, Satterfield-Doerr M, Parikh AR and Brodbelt JS (1998) Analytical Chemistry 70: 1788.Copyright American Chemical Society.)
urine samples. A 65-�m Carbowax/DVB Rbre wassuitable for the extraction of these drugs. The detec-tion limits reached 1 ng mL�1. Okeyo et al. developeda straightforward method for performing derivatizingreactions of Rve steroids in situ in SPME Rbres. Afterextraction of drugs from serum samples by direct im-mersion SPME, the drugs extracted on 85-�m PA Rbrewere derivatized in the headspace of the silylatingreagent bis(trimethylsilyl)triSuoro-acetamide, andthen analysed by GC/MS. With derivatization, SPMEand GC analysis can be easily extended to the analysisof semi- and non-volatile compounds.
Volmer and Hui developed a SPME/LC/MSmethod for isolating and analysing eleven cor-ticosteroids and two steroid conjugates fromurine samples. After extraction in the vial by direct
immersion SPME using 65-�m Carbowax/DVBRbre, the drugs extracted in the Rbre were desorbedin the desorption chamber of the SPME/HPLCinterface, and then analysed by electrospray LC/MS.As shown in Figure 10, several corticosteroidsand steroid sulfates spiked in urine samples wereselectively analysed, although a minor peak wasobserved in the blank control urine in the SIM tracefor cortisone.
Furthermore, Kataoka et al. developed an auto-mated in-tube SPME/LC/MS method for the deter-mination of the histamine H2-receptor antagonistranitidine in urine samples. The ranitidine inurine samples was directly extracted into Omegawax250 capillary by 10 draw/eject cycles of 30 �L ofsample at pH 8.5, desorbed from the capillary with
4166 III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications
Figure 10 SPME/LC/MS analysis of several corticosteroids and steroid conjugates by time-scheduled SIM. The original urinesample was spiked at the 20 mg mL�1 level. (A) Blank control urine; (B) spiked urine. LC/MS conditions: column, YMC ODS-AQ (50mm �4.0 mm i.d., 3 �m particle size); column temperature, 253C; mobile phase, A"100 mM ammonium acetate and B"acetonit-rile/methanol (50 : 50: #100 mM ammonium acetate), A : B was gradient programmed from 60 : 40 to 20 : 80 in 10 min; flow-rate,1 mL min �1; fragmentor voltage, 40 V; ionization mode, negative ESI. SPME conditions: fibre, 65 �m carbowax/DVB; sample pH, 8.5;extraction, immersion for 15 min with stirring; desorption, methanol/water (50 : 50) for 5 min. Peaks: 1, estriol-3-sulfate; 2, cortisone; 3,fludrocortisone; 4, estrone-3-sulfate; 5,6-methylprednisolone; 6, budesonide (epimer B); 7, budesonide (epimer A); IS"internalstandard (niflumic acid) at 20 �g mL�1. (Reproduced with permission from Volmer DA and Hui JPM (1997) Rapid Communications inMass Spectrometry 11: 1926. Copyright John Wiley & Sons Limited.)
methanol, and then analysed by electrospray LC/MS.Using this technique, nine beta-blockers and metab-olites in urine and serum samples were also analysed.These methods were simple, rapid, selective and sen-sitive, and directly applied to urine samples andserum samples after ultraRltration. Propranolol (PL)and its metabolites were successfully detected in theserum sample of a patient administrated PL (seeFigure 11).
Prospective of SPME in BiomedicalAnalysis
The main advantages of SPME are simplicity, rapid-ity, solvent elimination, high sensitivity, small samplevolume, lower cost and simple automation. Since1995, a number of SPME methods have been de-veloped to extract drugs from various biological sam-ples such as urine, serum, plasma, whole blood, saliva
III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications 4167
Figure 11 Total ion and SIM chromatograms obtained from standard propranolol and its metabolites, and a clinical serum sample byin-tube SPME/LC/MS. (A) Standard solution containing 200 ng mL�1 propranolol (PL), 50 ng mL�1 4-hydroxypropranolol (4-OH-PL)and 7-hydroxypropranolol (7-OH-PL), 20 ng mL�1 5-hydroxypropranolol (5-OH-PL) and N-desisopropylpropranolol (NDP). (B) Clinicalserum sample (100 �L). Serum sample was diluted five times with 1% acetic acid and used for analysis after ultrafiltration. LC/MSconditions: column, Hypersil BDS C18 (5.0 cm�2.1 mm i.d., 3 �m particle size); column temperature, 253C; mobile phase, acetonit-rile/methanol/ water/acetic acid (15 : 15 : 70 : 1); flow-rate, programme from 0.25 to 0.45 mL min�1 for 20 min run; fragmentor voltage,70 V; ionization mode, positive ESI; SIM ion, m/z "218 (NDP), 276 (hydroxypropranolols) and 260 (PL). In-tube SPME conditions:capillary, Omegawax 250 (60 cm�0.25 mm i.d., 0.25 �m film thickness); sample pH, 8.5; draw/eject cycles, 15; draw/eject volume,35 �L; draw/eject flow-rate, 100 �L min�1, desorption solvent, mobile phase. Peaks: 1, 5-OH-PL; 2, 4-OH-PL; 3, 7-OH-PL; 4, NDP; and5, PL. (Reproduced with permission from Kataoka H, Narimatsu S, Lord HL and Pawliszyn J (1999) Journal of Analytical Chemistry 71:4237. Copyright American Chemical Society.)
and hair. The afRnity of the Rbre coating for ananalyte is the most important factor in SPME. Asshown in Table 1, Rbre coatings of different polarityand thickness were selected for each drug. Most drugs
in biological samples were extracted with 100-�mPDMS for nonpolar drugs and 85-�m PA for polardrugs. A solvent-modiRed Rbre can improve selectiv-ity and shorten extraction time. Although the theories
4168 III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications
of Rbre and in-tube SPME methods are similar, thereare signiRcant differences between these methods.The extraction of analytes is performed on the outersurface of the Rbre for Rbre SPME and in the innersurface of the capillary for in-tube SPME. Commer-cially available SPME Rbres for drug analysis arelimited, by GC capillary columns with a vast array ofstationary phases are commercially available for in-tube SPME. Headspace Rbre SPME is suitable for theextraction of drugs in gaseous, liquid and solid sam-ples, because of the avoidance of contact with anaggressive matrix incompatible with the Rbre. Directimmersion Rbre SPME can be used to extract drugsfrom clear and cloudy liquid samples, however, in-tube SPME is limited to the extraction of clear liquidsamples. The headspace SPME technique, therefore,is suitable for direct extraction from whole bloodsamples, while immersion Rbre SPME or in-tubeSPME methods require deproteinization or ultraRl-tration of these samples prior to extraction. As men-tioned above, the extraction efRciency of Rbre SPMEdepends on extraction time, agitation, heating,sample pH and salt concentration. For in-tube SPME,number, volume and speed of draw/eject cycles, andsample pH are important factors for efRcient extrac-tion. On the other hand, the desorption of analytefrom a Rbre or capillary coating depends on thetemperature of the injection port and exposure timein combination with GC or GC/MS, or componentand volume of solvent when used in combinationwith HPLC or LC/MS. Therefore, these SPME para-meters should be optimized when developing a newSPME method for drug analysis.
With further development of new coating mater-ials, such as afRnity coatings for target drugs andchiral coatings for optically active drugs, the furtherdevelopment of derivatization methods, further coup-ling with different analytical instruments, such ascapillary electrophoresis, and improvement of theextraction and desorption conditions, the SPME tech-nique is expected to be widely applied in the futurefor highly efRcient extraction of drugs from variousbiological samples.
See also: II /Chromatography: Gas: Derivatization.Extraction: Solid-Phase Microextraction.
Further Reading
Battu C, Marquet P, Fanconnet AL, Lacassie E andLachatre G (1998) Screening procedure of 21 ampheta-
mine-related compounds in urine using solid-phasemicroextraction and gas chromatography}mass spectro-metry. Journal of Chromatographic Science 36: 1}7.
Degal F (1996) Comparison of new solid-phase extractionmethods for chromatographic identiRcation of drugs inclinical toxicological analysis. Clinical Biochemistry 29:529}540.
Eisert R and Levsen K (1996) Solid-phase microextractioncoupled to gas chromatography: a new method for theanalysis of organics in water. Journal of Chromato-graphy A 733: 143}157.
Junting L, Peng C and Suzuki O (1998) Solid-phase micro-extraction (SPME) of drugs and poisons from biologicalsamples. Forensic Science International 97: 93}100.
Kataoka H, Narimatsu S, Lord HL and Pawliszyn J (1999)Development of on-line in-tube solid-phase microex-traction/LC/MS system. Chromatography 20: 237}246.
Kroll C and Borchert HH (1998) Solid phase microextrac-tion (SPME) for sample preparation during drug meta-bolism studies. Pharmazie 53: 172}177.
Lord HL and Pawliszyn J (1998) Recent advances in solid-phase microextraction. LC-GC S41}S46.
Namera A, Yashiki M, Kojima T and Fukunaga N (1998)Solid phase microextraction in forensic toxicology.Japanese Journal of Forensic Toxicology 16: 1}15.
Pawliszyn J (1995) New directions in sample preparationfor analysis of organic compounds. Trends in AnalyticalChemistry 14: 113}122.
Pawliszyn J (1997) Solid Phase Microextraction: Theoryand Practice. New York: John Wiley.
Pawliszyn J (1999) Applications of Solid Phase Microex-traction. Cambridge, UK: The Royal Society ofChemistry.
Penton ZE (1997) Sample preparation for gas chromato-graphy with solid-phase extraction and solid-phasemicroextraction. Advances in Chromatography 37:205}236.
Sporkert F and Pragst F (2000) Use of headspace solid-phase micro-extraction (HS-SPME) in hair analysis fororganic compounds. Forensic Science International 107:129}148.
Ulrich S and Martens J (1997) Solid-phase microextractionwith capillary gas}liquid chromatography and nitro-gen}phosphorus selective detection for the assay of anti-depressant drugs in human plasma. Journal ofChromatography B: Biomedical Applications 69:217}234.
Volmer DA and Hui JPM (1997) Rapid determination ofcorticosteroids in urine by combined solid-phase micro-extraction/liquid chromatography/mass spectrometry.Rapid Communications in Mass Spectrometry 11:1926}1934.
Zhang Z, Yang MJ and Pawliszyn J (1994) Solid phasemicroextraction: a new solvent-free alternative forsample preparation. Analytical Chemistry 66:844A}853A.
III / SOLID-PHASE MICROEXTRACTION / Biomedical Applications 4169