Photophysics and photochemistry of z-chlorprothixene in acetonitrile

Article abstract of DOI:10.1111/j.1751-1097.2009.00584.x

Chlorprothixene (CPTX, Taractan) is a low potency antipsychotic mainly used for the treatment of psychotic disorders (e.g. schizophrenia) and acute mania occurring as part of bipolar disorders. As in the case of other numerous drugs used in the

Full text of DOI:10.1111/j.1751-1097.2009.00584.x

Photochemistry and Photobiology, 2009, 85: 895–900
Photophysics and Photochemistry of z-Chlorprothixene in Acetonitrile†
1,2
Luis E. Pinero , Carmelo Garcıa* , Virginie Lhiaubet-Vallet , Rolando Oyola and Miguel A. Miranda
1
2
1
2
˜
´
1Department of Chemistry, University of Puerto Rico at Humacao, Humacao, Puerto Rico, USA
2
´
´
´
Instituto de Tecnologıa Quımica UPV-CSIC, Universidad Politecnica de Valencia, Valencia, Spain
Received 2 January 2009, accepted 7 April 2009, DOI: 10.1111/j.1751-1097.2009.00584.x
Under UVA irradiation, this derivative also undergoes a rapid
Z ⁄ E photoisomerization. Furthermore, prolonged exposure to
light with k<350 nm causes the alkylamino chain split off,
producingthe correspondingthioxanthone (2). Although CPTX
is prescribed as a pure Z-eutomer, the introduction of the
E-isomer can alter its pharmacokinetics and intensify the
phototoxic response to this drug. Stereoisomers have been
shown to differ in the plasma-time profiles, degree of interaction
with receptors, clearance rate from the body, and bioactivity.
zCPTX is by far physiologically more active than the E-isomer
(3). Nevertheless, there are no reports on the efficiency of the
photoisomerization, the parameters affecting this process, nor
on the rationale for the mechanism for the formation of the
thioxanthone. In this work, the Z ⁄ E isomerization quantum
yields were measured for zCPTX and its hydrochloric salt in
aerobic and anaerobic environment. Furthermore, the photo-
physics of this drug was better characterized and a mechanism is
proposed for its decomposition into CTX.
ABSTRACT
Chlorprothixene (CPTX, Taractanꢀ) is a low potency antipsy-
chotic mainly used for the treatment of psychotic disorders (e.g.
schizophrenia) and acute mania occurring as part of bipolar
disorders. As in the case of other numerous drugs used in the
treatment of psychiatric disorders, CPTX presents geometric
isomerism. Therefore, in vitro irradiation induces a rapid Z ⁄ E
isomerization, which can affect its pharmacokinetic properties.
This photoisomerization is not dependent on the oxygen concen-
tration. The Z ⁄ E quantum yields determined for zCPTX in
acetonitrile are 0.22 and 0.21 in anaerobic and aerobic environ-
ments, respectively. In the presence of water, both isomers
decompose to produce 2-chlorothioxanthone (CTX) after pro-
longed irradiation. This process strongly depends on the water
concentration and the irradiation time, i.e. it is autocatalyzed by
the CTX through a triplet-energy transfer mechanism. The
protonation state of the terminal amino group, on the other hand,
has no effect on the isomerization process, but inhibits the
formation of CTX. These results indicate that the phototoxicity
of zCPTX is somehow affected by the formation of CTX.
MATERIALS AND METHODS
Chemicals. The Z-isomer of 2-chloro-9-(3-dimethylaminopropylidene)-
thioxanthene hydrochloride (CPTX–HCl, Fig. 1), promazine
hydrochloride (PZ–HCl) and 2-chloro-9-thioxanthone (CTX) were
purchased from Sigma–Aldrich (St. Louis, MO). Organic solvents
(Fisher, PR) were of high quality spectrophotometric grade and other
chemicals were from well-known suppliers and used without further
purification. Nitrogen and helium were purchased from Air Products
(Humacao, PR). Aqueous solutions were prepared with nanopure
deionized water. The free base of CPTX-HCl and PZ-HCl were
prepared by the addition of NaOH to an aqueous solution of the
protonated drug and then extracting with diethyl ether. The E-isomer
of CPTX was obtained from the batch photolysis of zCPTX and
separated using HPLC.
Absorption and emission spectroscopy. All absorption spectra were
taken using a HP 8453 UV–VIS photodiode array spectrophotometer.
The fluorescence spectra and the corresponding emission quantum
yields were determined using a Spex Fluorolog Tau 3 spectrofluorom-
eter (Horiba, NJ). The fluorescence quantum yields (uf) for CPTX
were determined relative to tryptophan (uf = 0.13) (4). The excitation
wavelength was 280 nm, the monochromator slits were set to 2.5 nm,
and the diluted reference and samples were optically matched
(A < 0.08). For CTX, the excitation wavelength was 340 and
thioxanthone (TX, u = 0.051) was used as reference (5). Corrections
were made for differences in the instrument sensitivity as a function of
wavelength, for differences in refractive index, and for intensity in the
excitation. The 0–0 singlet energy was obtained from the intercept of
the emission and the excitation spectra.
INTRODUCTION
The thioxanthene derivatives (Fig. 1), the structurally related
phenothiazines, along with the butyrophenones (phenylbutyl-
piperadines), diphenylbutylpiperadines, and the indolones
comprise the families of the so-called typical or conventional
psychotics. As a group, they are dopamine receptor antago-
nists with a higher affinity for D2 over D1 receptors. The main
differences between them are the type and severity of side-
effects. Most of their side-effects are predictable, based on the
relative strength of interaction between the drug and the
different neurotransmitter receptors. Depending on their
specific receptor binding profiles, all these antipsychotics may
produce, among others: sedation, urinary retention, dry
mouth, blurred vision, sinus tachycardia, and phototoxicity
(1). Photoinduced eruptions are well-known adverse effects of
several neuroleptic drugs. UVA in vitro photohemolysis test
demonstrated that chlorprothixene (CPTX) is one of the most
phototoxic antipsychotics.
For the thioxanthene derivatives, a 2-substituent introduces
Z ⁄ E geometrical isomers at the exocyclic 9-olefin function.
Steady-state photolysis and quantum yield. The photochemistry of
zCPTX was studied with a 1000 Watt high pressure mercury–xenon
lamp (Sylvania). The 313 nm line was isolated with a 1 ⁄ 8 m grating
monochromator (Spectra Physics). The lamp intensity at this
wavelength was measured before and after each photolysis. All
†This invited paper is part of a Symposium-in-Print on Pharmaceutical
Photochemistry.
*Corresponding author email: carmelo.garcia@upr.edu (Carmelo Garcıa-Ruiz)
´
ꢁ 2009 The Authors. JournalCompilation. The AmericanSocietyofPhotobiology 0031-8655/09
895

896 Luis E. Pin˜ero et al.
ð2Þ
Figure 1. Structure of the thioxanthene derivatives used for this work.
photoreactions were carried out at room temperature using a quartz
a maximum of 50%
RESULTS AND DISCUSSION
cuvette (1 · 1 · 4 cm3) and extended to
conversion of the starting material. The reaction mixtures were
continuously stirred during irradiation and analyzed with a HPLC
to determine the conversion percent and the yields of isomerization.
For the determination of the Z ⁄ E quantum yield, 3 mL of 0.09 mM
helium saturated solutions of zCPTX were irradiated at 313 nm.
The irradiation time was controlled with an electronic shutter and
an in-house program based on LabView 8.0 (National Instruments,
TX). After completion of each photolysis, 45.5 lL of a 4.15 mM
solution of PZ was added as internal standard. Then 10 lL of this
mixture was injected at least three times into the HPLC to
determine the quantity of remaining starting material. The quantum
yield was then calculated as explained elsewhere (6). Briefly,
the slope of the linear part of the concentration–time curve is equal
to the rate of the zeroth-order reaction (k), V is the irradiated
volume (3 mL), I0 is the lamp intensity at 313 nm, [zCPTX]0 is the
initial drug concentration, and a is the fraction of zCPTX that has
reacted. The quantum yield is then obtained with the following
equation:
Ground and excited state properties
The absorption spectra of zCPTX and its hydrochloric salt
show three broad bands at 229, 269 and 324 nm (Fig. 2 and
Table 1). Almost no difference is observed between these
spectra and the spectrum of the E-isomer, which shows
maxima at 273 and 322 nm. The small differences are
introduced by the difference in the abcd torsion angle of the
thioxanthene system (Fig. 1). The DFT calculated torsion
angles are 137.5 and 139.6ꢂ for the Z and E isomer,
respectively. The 324 nm band is produced by the combination
of an n fi p* (n-electrons of the chlorine atom) and a p fi p*
transition (exocyclic double bond) (Fig. 2, inset). The p fi p*
contribution is relatively large and is the one responsible for
the Z ⁄ E isomerization. The 269 nm band includes the same
transitions, but with a larger p fi p* contribution. This
explains why photoisomerization is observed only with UVA
irradiation (9).
The emission spectra of CPTX and its salt consist of a single
broad band with a maximum at 393 and 399 nm, respectively
(Fig. 3 and Table 1). The intensity dependence on the excita-
tion wavelength clearly shows that the emission is almost
completely generated by the 324 nm band. The excitation with
250–280 nm, corresponding to the excitation of the p-elec-
trons, does not form part of the fluorophore (Fig. 3, Curve a).
The dependence of the fluorescence quantum yield on the
ꢀ
-d[zCPTXꢁ=dtÞV
ꢀdn
1
ꢀkV
/
¼
¼
¼
Isom:
dt Iabs: I0ð1 ꢀ 10ꢀeb½zCPTXꢁÞ
I0ð1 ꢀ 10ꢀeb½zCPTXꢁ ð2ꢀaÞ=2
Þ
0
ð1Þ
The concentration of zCPTX is obtained from calibration curves
and the division by 2 in the fraction of light absorbed is included to
account for the gradient produced in the Iabs term, i.e. the absorbed
intensity is taken as the average of the initial and final absorption.
Absorption spectra were taken for all solutions before and after each
irradiation.
High performance liquid chromatography. The chromatographic
separations were done using a protocol similar to the one described
by Li-Wan et al. (7). The chromatograms were taken with an Agilent
Technologies 1200 chromatograph. The instrument parameters were
set to: flow rate = 0.500 mL min)1; Degasser = G1322A; Autosam-
pler = G1313A; Detector = diode array UV–Vis G1315B set at
260 nm. The photoproducts were separated with a 250 · 4.6 mm i.d.
5 lM Partisil C8 reverse phase column (Waters). The mobile phase
was composed of ethyl acetate, methanol and 3% ammonium
hydroxide (84:15:1).
concentration of zCPTX was prepared using
A
calibration curve of amount ratio vs.
range of 0.02–
a
0.12 mM and a constant concentration of 0.062 mM of the internal PZ
standard. All solutions used for the calibration were injected three
times and the average of the integrated area was used for the curve.
All integrations and calculations were done with the HP–ChemSta-
tion software.
Theoretical calculations. Density functional calculations (DFT)
were performed to obtain relative energies for zCPTX and its
derivatives. The geometry pre-optimizations were performed in vacuo
with the PM3 semiempirical method using the Polak-Ribiere conju-
)1
gated gradient protocol (1 · 10)5 convergence limit, 0.01 kcal A
*
˚
mol RMS-limit) (8). The final optimizations were performed with DFT
[B3LYP ⁄ 6-31G(d) OPT SCRF = (PCM, Solvent = acetonitrile)]
using Gaussian 03 at the High Performance Computing Facility
(UPR Rio Piedras). All conformational and thermodynamical param-
eters were obtained with a DFT single point calculation. The energy
associated with each of the processes in Eq. (2) was obtained as the
Figure 2. Absorption spectra of zCPTX-HCl (s) and its free base (n)
in acetonitrile. Inset: Transitions of the molecular orbitals responsible
for the 324 nm band.
difference of the hartree energy in vacuo or in solution [DE (kcal mol)1
= (EPROD–EREACT)*627.51]:
)

Photochemistry and Photobiology, 2009, 85 897
Table 1. Photophysical properties of zCPTX and zCPTX–HCl in acetonitrile.
Absorption
Emission
kmax
(nm)
2
kmax
(nm)
2
Stoke’s shift
(cm)1
7
ES
0.4
Compound
zCPTX
log e
4.55
0.03
)
uf
0.2 · 103
(kcal mol)1
)
229
269
324
232
270
328
221
259
292
305
386
393
399
415
5419
3.4
80.4
4.19
3.58
4.52
4.13
3.50
4.22
4.59
3.68
3.65
3.77
zCPTX–HCl
CTX
5425
1743
2.2
8.0
79.3
71.5
The quantum yields were determined using an excitation wavelength of 280 nm.
Figure 3. Normalized excitation and emission spectra of zCPTX in acetonitrile (Left) and the corresponding quantum yield (Right). The emission
was measured at 393 nm using excitation wavelengths from (a) 250 nm to (j) 340 nm with a 10 nm increment.
excitation wavelength (Fig. 3, Right) illustrates how the
excitation into the precursor state to isomerization results in
significantly lower fluorescence. The excitation spectrum
reproduces the absorption maxima (269 and 324 nm), but
not the corresponding intensity. The diminishing of the
269 nm band confirms, once again, that it is associated with
other transitions. A large bathochromic effect is observed for
both CPTX and CPTX–HCl. This relative large Stokes shift is
probably due to the charge transfer character of the emission
or to an excited state solvent interaction, because the ground
state absorption process is solvent-independent.
An excited singlet energy of ꢂ79 kcal mol)1 was obtained
for zCPTX–HCl and its free base from the crossing point of
the normalized excitation and emission spectra. Fluorescence
quantum yields of 0.0034 and 0.0022 were obtained for zCPTX
and zCPTX–HCl, respectively. These low uf values correspond
very well with those reported for the promazines (10) and
imipramines (6). As in the case of these structurally related
drugs, fluorescence is not the major S1 deactivation process for
CPTX.
the absence of oxygen, a rapid Z ⁄ E photoisomerization takes
place. In the presence of oxygen, on the other hand, the
isomerization occurs along with the formation of an oxidation
compound (CTX). For the formation of this compound, they
proposed a photoreaction between air-oxygen and the CPTX
triplet excited state (3CPTX*). The mechanism proposed for
this reaction includes the 1,4-sigmatropic rearrangement of
3CPTX*, producing an enamine derivative. This intermediate,
according to these authors, hydrolyzes to yield CTX. They
further found that irradiation under a nitrogen atmosphere
caused a slow degradation from the Z to the E isomer with the
formation of a small amount of an unidentified compound.
Quantum yields for these processes were not reported, since
monochromatic light was not used for the irradiations.
The photodecomposition of zCPTX and zCPTX–HCl
studied in this work follows a first order mechanism in
acetonitrile (Fig. 4, Inset). Under anaerobic conditions, the
absorption decreases at 324 nm with irradiation time, while
increases at 250 and 380 nm (Fig. 4). This produces two
isosbestic points at 310 and 345 nm (and several others at
shorter wavelengths). Under the same conditions, the photol-
ysis of CPTX–HCl produces similar changes in absorption, but
the kinetic is much slower than for CPTX, and no increase at
380 nm is observed (data not shown). This inhibition induced
by the protonation indicates that the terminal amino group is
Steady-state photolysis
The photochemistry of zCPTX–HCl in water was previously
reported by Li-Wan et al. (2). These authors observed that, in

898 Luis E. Pin˜ero et al.
(2), but by the dissolved water molecules. This was confirmed
by changing the water content in acetonitrile, the smaller the
water content, the smaller the total absorption changes at
385 nm (data not shown).
The theoretical DFT calculations corroborate that the
process xCPTX + H2O fi CTX + CH2 = CH2 + N(CH3)3
is thermally favorable. Enthalpy changes of –40.6 kcal mol)1
and –39.7 kcal mol)1 were obtained for zCPTX and eCPTX,
respectively. Slightly higher values (–45.0
0.4 kcal mol)1
)
were obtained in vacuo, because ethene and trimethyl amine
are not stabilized by the solvent as much as the other
compounds. They have solvation enthalpies of only )0.9 kcal
mol)1 and )0.3 kcal mol)1, respectively. The triplet state of
both CPTX isomers, on the other hand, have enthalpies of
)6.2 kcal mol)1; the CTX product has a ‘‘stabilization’’
enthalpy of )7.8 kcal mol)1; and water has )7.4 kcal mol)1
.
Furthermore, the extent of the Z ⁄ E isomerization does not
depend on the atmosphere used for the photolysis. The
amount of CTX, on the other hand, increases with irradiation
time 2–3 times faster under nitrogen (Fig. 6). This behavior is
explained in terms of a triplet energy transfer from CTX to
CPTX. Under aerobic conditions, both triplets (3CPTX* and
3CTX*) are quenched by oxygen. Therefore, the energy
transfer has to compete with the triplet quenching and only
a small increase in the formation in CTX is observed.
Moreover, the sensitization ⁄ autocatalytic phenomenon is
observed under nitrogen after ꢂ50% conversion of the initial
material (Fig. 6). This is the time required for the accumulated
CTX to be able to compete for the absorption of the 313 nm
light. If CTX is added to the reaction mixture, the increase in
its concentration is observed from the very beginning of the
photolysis, especially if the irradiation is done at its absorption
maximum of 385 nm (Fig. 6). These observations can be
summarized in a general mechanism for the formation of CTX
and the sensitization of the decomposition of zCPTX (Fig. 7).
According to this mechanism, the kinetics for the formation
of CTX is given by the following equation (x = Z or E):
Figure 4. Absorption spectra for the photolysis of 0.0193 mM zCPTX
in acetonitrile under anaerobic conditions at 313 nm (A313 = 0.060).
A time interval of 600 s was used to record each spectrum with
t(a) = 0 s. Inset: Concentration ⁄ Time plot for the photolysis of
zCPTX in acetonitrile under anaerobic conditions irradiated with
313 nm (A313 = 0.25, I0 = 6.61 · 10–9 E s)1). The dashed line repre-
sents the linear regression for 0–120 s.
somehow involved in the photodestruction mechanism. The
quantum yields measured for the Z ⁄ E isomerization of CPTX
(measured at the beginning of the photoreaction) were 0.22 in
nitrogen and 0.21 in air.
The photolysis of zCPTX in acetonitrile also produces one
product at short irradiation times and a second one after
prolonged irradiation. Both photoproducts were identified
from their absorption spectra taken with the HPLC–UV
detector and known references (Fig. 5, Inset). The 385 nm
band is clearly assigned to CTX. Nevertheless, it was found
that this compound is formed in large quantities under
anaerobic conditions. This fact indicates that its formation is
not mediated by the air oxygen, as proposed by Wan-Po et al.
Figure 5. Absorption spectra of the photoproducts of zCPTX in
acetonitrile under saturated air conditions at 313 nm. The spectra
correspond to the chromatographic fractions shown in the inset:
(s, CTX) 6.53 min; (,, cCPTX) 7.47 min; and (h, eCPTX) 8.01 min.
Inset: HPLC chromatogram after 1 h photolysis of zCPTX in
acetonitrile with a 1000 W lamp.
Figure 6. Kinetic curves for the 313 nm photolysis of 0.019 mM
zCPTX in nitrogen (m) and air (n). Kinetic curves for the 400 nm
photolysis of a mixture of 0.0069 mM CTX and 0.069 mM zCPTX in
nitrogen (d) and air (r). All absoption measurements were done at
385 nm.

Photochemistry and Photobiology, 2009, 85 899
Figure 7. General mechanism for the Z ⁄ E isomerization of xCPTX and the decomposition to CTX. The photoproduct CTX catalyzes the
photodestruction of xCPTX through an energy transfer mechanism. The same triplet state is proposed for both isomers of CPTX. The energy
transfer to zCPTX is not shown for clarity.
Figure 8. Mechanism for the formation of CTX from xCPTX in acetonitile under a nitrogen atmosphere.

900 Luis E. Pin˜ero et al.
CTX
!
ꢁ
ꢂ
xCPTX
ISC
þkxSCPTX þk
X
d½CTXꢁ
chemistry of zCPTX is the same in both solvents. It was also
demonstrated that CTX is produced by the reaction of
3CPTX* with solvent water molecules and not with oxygen.
These results were obtained by exciting CPTX either directly
or by sensitization with thioxanthone. Our results suggest that
the zCPTX amino side-chain protonation plays a crucial role
in CTX formation, because CPTX-HCl never produces this
derivative, even after very long irradiation times. Finally, it
was shown that CTX autosensitizes its own formation,
k
kr½H2Oꢁ
xCPTX
¼
I
abs
xCPTX
ISC
xCPTX
isom
dt
K
kr½H2OꢁþkxTCPTX
x¼Z;E
ꢁ
ꢂꢁ
ꢂꢁ
ꢂ
k
kET½CPTXꢁ
kr½H2Oꢁ
CTX
abs
ISC
þI
CTX
ISC
k
þkSCTX kET½CPTXꢁþkTCTX
kr½H2OꢁþkxTCPTX
ð3Þ
withks ¼kf þksd;kT ¼kp þkdT
Using [zCPTX]0 = [CTX] + [xCPTX] and the Beer–
Lambert’s law, this expression takes the simpler form:
3
increasing the formation of CPTX*. Therefore, the autosen-
ꢀ
ꢃ
ꢀ
ꢃ
b ½zCPTXꢁ0 ꢀ ½CTXꢁ ½CTXꢁ
d½CTXꢁ
dt
sitization of CTX may play a key role in the zCPTX
phototoxicity, because: (a) it is part of the damaging metabolic
products of zCPTX; (b) thioxanthones photoreact easily from
the singlet and the triplet state; and (c) CTX autosensitizes
its own formation, increasing the formation of 3CPTX*
and—thus—the toxic potency of zCPTX.
ꢀ
ꢃ
¼ a ½zCPTXꢁ0 ꢀ ½CTXꢁ þ
ð4Þ
c þ d ½zCPTXꢁ0 ꢀ ½CTXꢁ
where a, b, c, and d are the collections of the corresponding
rate constants (for a constant water concentration). The plot of
this function ([CTX] vs. t) reproduces very well the experi-
mental dependence of the CTX absorption with irradiation
time in nitrogen (Fig. 6). Since in the presence of oxygen the
energy transfer is not possible, there is less production of CTX
(kET = 0). In this case, Eq. (3) gives a linear relationship
between [CTX] and time, as shown in the same figure.
The HPLC chromatograms of all reaction mixtures con-
taining zCPTX show the formation of both eCPTX and CTX
(Fig. 4, inset), but only the E-isomer is formed if zCPTX–HCl
is irradiated (data not shown). A mechanism is proposed,
which involves the terminal amino group in the formation of
CTX (Fig. 8). The Z ⁄ E isomerization is proposed to occur
from the singlet state, since no effect of dissolved oxygen was
observed for this process. After intersystem crossing, the triplet
state reacts with the water molecule to produce an intermediate
tertiary alcohol. This intermediate, in turn, breaks into more
stable molecules (ethene, trimethylamine and CTX) through
an intramolecular process. In this process the alcohol is
attacked by the nonbonding electrons of the terminal amino
group. In the photochemistry of CPTX–HCl, no CTX
formation is observed, because these electrons are no more
available.
Acknowledgements—This work has been supported in part by NIH-
MBRS Grant SO6GM08216 to UPR-Humacao. We specially thank
the High Performance Computing Facility at UPR Rio Piedras for the
help with the theoretical calculations and Dr. Rafael Arce (UPR, Rio
Piedras) for the many helpful discussions.
REFERENCES
1. Dufner, K. S., L. A. Buss and K. Kizito (2006) Drug-induced
photosensitivity. Hospital Pharm. 41, 196–206.
2. Li-Wan, P. A. and W. J. Irwin (1980) The photochemical stability
of Z– and trans– isomers of tricyclic neuroleptic drugs. J. Pharm.
Pharmacol. 32, 25–29.
3. Enna, S. J., J. P. Bennett, D. R. Burt, I. Creese, D. C. U’Prichard,
D. A. Greenberg and S. H. Snyder (1977) Stereospecificity and
clinical potency of neuroleptics. Nature 267, 184.
4. Lakowicz, J. R. (1999) Principles of Fluorescence Spectroscopy
Kluwer. Academic ⁄ Plenum Publishers, New York, NY.
5. Dalton, J. C. and F. C. Montgomery (1974) Solvent effects on
thioxanthone fluorescence. J. Am. Chem. Soc. 96, 6230–6232.
˜
6. Garcıa, C., R. Oyola, L. E. Pinero, D. Hernandez and R. Arce
´ ´
(2008) Photophysics and photochemistry of imipramine,
desimipramine and clomipramine in several solvents: A fluores-
cence, 266 nm laser flash and theoretical study. J. Phys. Chem. A
112, 168–178.
CONCLUSIONS
7. Li-Wan, P. A. and W. J. Irwin (1979) A high performance liquid
chromatographic assay of Z- and trans-isomers of tricyclic
neuroleptic drugs. J. Pharm. Pharmacol. 31, 512–516.
8. Jouyban, A. and B. H. Yousefi (2003) A quantitative structure
property relationship study of electrophoretic mobility of analytes
in capillary zone electrophoresis. Comp. Biol. Chem. 27, 297–303.
9. Eberlein-Konig, B., A. Bindl and B. Przybilla (1997) Phototoxic
properties of neuroleptics drugs. Dermatology 194, 131–135.
Chlorprothixene is metabolized by side chain N-demethylation
and by sulphoxidation. In addition, CTX and other xanthone
derivatives are minor products excreted in the urine (11). Since
CPTX is structurally related to chlorpromazine, they share all
side-effects, including the phototoxicity. As in the case of the
related promazines and imipramines, the phototoxicity mech-
anism is unknown. Moreover, the mechanism for the forma-
tion of CTX from CPTX is also unknown.
10. Garcı
´
V. Sa
˜
a, C., R. Oyola, L. E. Pinero, R. Arce, J. Silva and
nchez (2005) Substitution and solvent effect on the photo-
´
physical properties of several series of 10-alkylated phenothiazine
derivatives. J. Phys. Chem. A 109, 3360–3371.
11. Abernathy, C. O. and H. J. Zimmerman (1975) The toxicity of
thioxanthene neuroleptics to isolated rat liver cells. Proc. Soc.
Exp. Biol. Med. 150, 385–389.
In this work, we studied the photochemistry of zCPTX in
aqueous and water ⁄ acetonitrile solvent under aerobic and
anaerobic conditions. Our results established that the photo-