Journal of Analytical Toxicology 2014;38:242 –248
doi:10.1093/jat/bku025 Advance Access publication March 28, 2014
Applying Quantitative Structure–Activity Relationship (QSAR) Methodology for Modeling
Postmortem Redistribution of Benzodiazepines and Tricyclic Antidepressants
Constantinos Giaginis1*, Anna Tsantili-Kakoulidou2 and Stamatios Theocharis3
1
Department of Food Science and Nutrition, School of Environment, University of the Aegean, Mitropoliti Ioakeim 2 Street, Myrina,
Lemnos GR 81400, Greece, 2Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, Panepistimiopolis,
Zografou, Athens 157 71, Greece, and 3First Department of Pathology, Medical School, University of Athens, Athens, Greece
*Author to whom correspondence should be addressed. Email: cgiaginis@aegean.gr
Postmortem redistribution (PMR) constitutes a multifaceted process,
which complicates the interpretation of drug concentrations by foren-
sic toxicologists. The present study aimed to apply quantitative struc-
ture –activity relationship (QSAR) analysis for modeling PMR data of
structurally related drugs, 10 benzodiazepines and 10 tricyclic antide-
pressants. For benzodiazepines, an adequate QSAR model was
obtained (R 2 5 0.98, Q 2 5 0.88, RMSEE 5 0.12), in which energy,
ionization and molecular size exerted significant impact. For tricyclic
antidepressants, an adequate QSAR model with slightly inferior sta-
tistics (R 2 5 0.95, Q 2 5 0.87, RMSEE 5 0.29) was established after
exclusion of maprotiline, in which energy parameters, basicity char-
acter and lipophilicity exerted significant contribution. Thus, QSAR
analysis could be used as a complementary tool to provide an inform-
ative illustration of the contributing molecular, physicochemical and
structural properties in PMR process. However, the complexity, non-
static and time-dependent nature of PMR endpoints raises serious
concerns whether QSAR methodology could predict the degree of
redistribution, highlighting the need for animal-derived PMR data.
Introduction
The interpretation of drug concentrations in postmortem period
constitutes one of the most difficult aspects in the field of foren-
sic toxicology. This is mainly ascribed to the fact that drug
concentrations obtained from postmortem samples do not ne-
cessarily reflect the blood concentration at the time of death
due to variations according to the sampling site and the interval
between death and sampling (1 – 5). These site- and time-
dependent variations have been attributed to a multifaceted pro-
cess occurring after death, referred to as postmortem redistribu-
tion (PMR) (6, 7). The high complexity of PMR process is
amplified by the fact that it does not exclusively refer to fatal poi-
soning, but it may also reflect antemortem physical or biochem-
ical alterations. Many drugs are sequestered antemortem in
organs qualified as drug reservoirs. Hollow organs with high con-
centrating power, such as different parts of the gastrointestinal
tract or viscera, liver, lungs and heart, can function as drug reser-
voirs (6 –8). Redistribution from these organs can occur by diffu-
sion through blood vessels and/or transparietal diffusion toward
surrounding organs (6 –8). The competing processes of diffusion
from drug reservoirs, disruption of cellular membranes and
putrefaction may lead to alterations in drug concentrations be-
tween sites and sampling intervals (9, 10). Drugs biotransforma-
tion by metabolizing enzymes, such as cytochrome P450
monooxygenases and/or uridine diphosphate-glucuronosyl-
transferases, could also be triggered at an early stage of
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Article
postmortem period (11). Consequently, PMR of drugs may com-
plicate the interpretation of the analytical results in forensic toxi-
cology and has emergently been considered as ‘a toxicological
nightmare’ (10, 12).
Quantitative structure – activity relationship (QSAR) method-
ology is a useful tool for analyzing in a systematic way the infor-
mation incorporated in the chemical structure of compounds in
relation to the available biological data (13, 14). This method-
ology has widely been accepted to evaluate and predict the activ-
ity of drugs against a therapeutic target, as well as the toxicity
risk assessment of drugs or chemicals, supporting the reduction,
refinement and/or replacement of experimental studies (15 –
17). Currently, relevant software packages are available, which
permit the calculation of a large number of physicochemical, mo-
lecular and structural descriptors, facilitating their elaboration in
QSARs as an alternative strategy for the establishment of predict-
ive models (14–16). In the last few years, multivariate data ana-
lysis (MVDA), a projection method to latent variables, the
principal components, which are linear combination of the ori-
ginal descriptors, has widely been applied to QSAR modeling
(18, 19). MVDA has been considered as a powerful statistical
tool, which can treat a large number of interrelated descriptors,
exploiting the maximum information encoded within them and
separating regularities from noise (18, 19). Moreover, MVDA per-
mits the elaboration of descriptors and response variables, in
which the high accuracy of computational and experimental
values is not an emergent requisite in contrast to conventional
statistical methods (18, 19).
Physicochemical properties are considered to play a crucial
role in pharmacokinetics, mainly in absorption and distribution,
as well as in the pharmacodynamic and toxicological profile of
drugs (20, 21). Among them, lipophilicity, ionization and
volume of distribution were reported to affect the ability of
drugs to redistribute across the tissue barriers during post-
mortem period (22 – 24). In a previous work by our group, we
effectively applied QSAR methodology to model PMR of struc-
turally diverse drugs (25). The derived QSAR model provided an
informative illustration of the contributing molecular, physico-
chemical and structural properties of drugs in the PMR process
(25). However, this model presented moderate predictive
power and limited applicability, which was ascribed to the
high complexity of the PMR process and the structurally diver-
sity of the data set (25). In view of above considerations, the
present study aimed to develop more specific QSAR models
using two structurally homogeneous data sets, benzodiazepines
and tricyclic antidepressants, which attract special attention in
the field of forensic toxicology.
 Methods and materials
Data set
The data set consisted of two chemical classes of compounds, 10
benzodiazepines and 10 tricyclic antidepressants. The extent of
PMR expressed by the central : peripheral concentration ratio
(C : P ratio) was taken from the literature (22).
Descriptors
Structural specific constitutional descriptors were derived manu-
ally. Structural specific constitutional descriptors include the
total number of rings (nRings), the number of aromatic rings
(nArC6), the number of heteroatoms into the rings, such as the
number of nitrogen (nNr), oxygen (nOr) and sulfur atoms (nSr),
the sum of nitrogen and oxygen atoms (nNOr) and the sum of
nitrogen, oxygen and sulfur atoms (nNOSr), the number of het-
eroatoms out of the rings (nNnr, nOnr, nSnr, nNOnr and NOSnr),
as well as the total number of heteroatoms (nN, nO, nS, nF, nCl
and nHal) and the number of double bonds (nC¼C). The
descriptors nRings and nArC6 constitute a measure of the size
of a molecule. The number of nitrogen (nN), oxygen (nO), sulfur
(nS) and fluoride (nF) constitute a measure of the polarity of a
molecule, reflecting hydrogen-bonding capability. The number
of halogens (nHal) and chlorides (nCl) reflect the hydrophobi-
city of compounds (16, 25).
Physicochemical and molecular properties, such as lipophili-
city (logarithm of octanol – water partition coefficient 2log P
for the neutral form, logarithm of octanol –water distribution co-
efficient 2log D5.5 and log D7.4 if ionized molecular species are
present at pH 5.5 and 7.4, respectively), number of hydrogen
bond acceptor and donor sites, number of rotatable bonds
(nRB) that expresses the flexibility of a molecule, ionization con-
stant ( pKa), topological polar surface area and molecular weight,
were calculated with ADME Boxes 3.0 (Pharma-Algorithms,
Toronto, Canada). The number of acidic (aIon) and basic
(bIon) ionizable groups was also deduced by ADME software.
The module Absolv implemented in the same software was
used to calculate Abraham’s solvatochromic parameters: hydro-
gen bond acidity (A), hydrogen bond basicity (B), excessive
molar refractivity (E), polarizability (S) and McGowan volume
(Vmc). For the calculation of lipophilicity corresponding to the
neutral species, additional software was used: ClogP (Biobyte
4.0), ChemDraw Ultra 9.0—logP(chem), according to Crippen
fragmentation (Cambridge Soft Corporation) and Pallas 3.3.2.4
(CompuDrug, International, Inc., Sedona, AZ, USA) and tried al-
ternatively in the analysis. ClogP (Biobyte 4.0) was selected as
the most appropriate to be incorporated in the final statistical
models. Boiling and melting points (BoilP and MeltP, respective-
ly), critical temperature (cTemp), pressure (cPres) and volume
(cVol), Gibbs energy (EGibbs) and Henry’s law (LHenry) were
deduced by ChemDraw (16, 25).
Threedimensional (3D) descriptors were calculated by
Hyperchem, v.5.0/Chemplus v.1.6 software. Energy minimization
was carried out by molecular mechanics using MMþ force field
followed by the semi-empirical AM1 method. The molecular
structures were constructed many times with different starting
points, and the robustness of the calculated parameters was eval-
uated. Molecular size parameters, such as solvent accessible and
van der Waals volume (SAVol and WAVol), solvent accessible and
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van der Waals surface area (SASA and WASA), as well as refractiv-
ity (Refr), polarizability (Pol) and dipole moment (Dipol 2X,
2Y, 2Z matrix), were calculated in the lowest energetic con-
formation. Energy parameters, such as the energy of the highest
occupied molecular orbital (EHOMO) and the energy of the lowest
unoccupied molecular orbital (ELUMO), which reflect the nucleo-
philicity and electrophilicity of a compound, respectively, the
energy gap: ELUMO – EHOMO, reflecting reactivity, as well as total
energy (Etotal ), binding energy (Ebinding), electronic energy
(Eelectr), nuclear energy (Enuclear) and heat of formation
(Heat.Form), were calculated by Hyperchem (16, 25). In total,
81 constitutional, 2D and 3D descriptors were calculated.
Multivariate data analysis
MVDA was performed using Simca-P 10.5 (Umetrics, CA, USA).
Prior to analysis, data were mean centered and scaled to unit
variance. Partial least squares (PLS) analysis was then applied to
obtain regression models (18, 19). In PLS analysis, PMR data were
treated as response variable Y. The derived models were validated
by different procedures: first, internal validation (cross-
validation) was performed using the default option of SIMCA-P,
namely by developing parallel models leaving out one group of
seven compounds each time. The omitted data are then consid-
ered as test set and the sum of squared differences between the
measured response and the predicted value, defined as predict-
ing residuals sum of squares (PRESS), is used to calculate cross-
validated correlation coefficient Q 2: Q 2 ¼ 12 PRESS/SSY. SSY
represents the variation in Y after mean centering and scaling.
This cross-validation procedure provides a more severe criterion
than the so-called leave-one-out approach since by decreasing
the size of CV groups the estimated Q 2 becomes very similar to
R 2. As a second tool, permutation testing was applied based on
the randomization of the response data (Y scrambling). The de-
fault option of SIMCA including 20 permutations was applied.
The proposed model was considered robust if the new models
on the set with randomized responses presented significantly
lower R 2 and Q 2 than the original model. In addition, as a more
critical test, randomized response data were used to run from the
beginning the model development procedure (26). Finally, exter-
nal validation was performed in the final model by splitting the
data set into several training and test sets. The root mean square
error of prediction (RMSEP) was considered for evaluating
predictive power.
Results
Benzodiazepines
PLS analysis was initially performed for the whole data set of ben-
zodiazepines (n ¼ 10), including all the descriptors. A two-
component PLS model with moderate statistics was derived
(R 2 ¼ 0.75, Q 2 ¼ 0.66, RMSEE ¼ 0.51). Nonoutliers were identi-
fied. A PLS model was further refined by variable selection
according to the variable influence to projection (VIP) criterion,
the weight (w) in the loadings plot and the size of the coeffi-
cients. Variables with VIP , 0.6 or low weight in the loading
plot and low coefficient were excluded. Among the descriptors
encoding the same information, those who performed better
were chosen. Finally, a three-component PLS model based on
QSAR Analysis in Forensic Toxicology 243
 10 original descriptors was obtained with N ¼ 10, R 2 ¼ 0.98, number of basic ionizable groups (bIon), as well as the number
Q 2 ¼ 0.88, RMSEE ¼ 0.12. In Table I, the observed and predicted of halogen (nHal) exerted considerable positive influence on the
PMR values, as well as the matching residuals, are included. model. Lipophilicity at pH 7.4 (log D7.4) and hydrogen-bonding
The VIPs and coefficients of the original descriptors are pre- donor capability contributed at a lower extent to the model.
sented as histograms in Figures 1A and B, respectively. Among The model was validated using a permutation test through ran-
the energy parameters, ELUMO – HOMO exerted the most important domly reordering response data. R 2 and Q 2 were plotted against
contribution to the model with a negative sign. Molecular size the correlation coefficient of the Y vector itself (Ry) yielding
descriptors, such as MR, Pol, SAVol and SASA, were found to be intercepts close (0.0, 0.401) and below (0.0, 20.219) zero,
important, exerting also negative impact on the model. On the respectively, indicating robustness of the model. Moreover, no
other hand, the ionization state of the drugs expressed by the significant model was obtained (R 2 , 0.2, Q 2 , 0.1), when the
entire model development procedure for the 10 compounds
was repeated with randomized response data (26). For external
Table I
validation, the same three-component PLS model was obtained
Observed PMR Data Taken from the Literature (22), Predicted PMR Data by QSAR Modeling and the
Matching Residuals for the Chemical Class of Benzodiazepines (RMSEE ¼ 0.12) for the training (n ¼ 8) set each time and successful PMR predic-
tions (0.08 , RMSEP , 0.28) were provided for the correspond-
Compounds PMRobs PMRpred PMRobs 2 PMRpred ing test set (N ¼ 2).
Alprazolam 1.5 1.6 20.1
Clonazepam 2.0 2.2 20.2
Clozapine 2.8 2.8 0.0
Diazepam 1.6 1.7 20.1
Flunitrazepam 3.0 3.0 0.0 Tricyclic antidepressants
Flurazepam 3.0 3.0 0.0
Midazolam 4.0 3.9 0.1
PLS analysis was initially performed for the whole data set (n ¼
Oxazepam 1.3 1.2 0.1 10), including all the descriptors. A two-component PLS model
Temazepam 1.6 1.5 0.1 with poor statistics was derived (R 2 ¼ 0.63, Q 2 ¼ 0.41,
Triazolam 2.8 2.8 0.0
RMSEE ¼ 0.88). Maprotiline was identified as extreme outlier

Figure 1. Histograms of (A) VIPs and (B) coefficients of the original descriptors used in the final PLS models for benzodiazepines. ELUMO – HOMO, energy of the lowest unoccupied
molecular orbital– energy of the highest occupied molecular orbital; Refr, refractivity; bIon, number of basic (bIon) ionizable groups; Etotal, total energy; Pol, polarizability; nHal, number
of halogens; SAVol, solvent accessible volume; SASA, solvent accessible surface area; log D7.4, logarithm of octanol– water distribution coefficient at pH 7.4; HBD, number of hydrogen
bond donor sites.

244 Giaginis et al.

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 presenting residuals for its predictive PMR value of .2 RMSEE. The VIPs and coefficients of the original descriptors included
After exclusion of maprotiline, refinement of the PLS model was in the final model are presented as histograms in Figure 2A and B,
performed, as previously described for benzodiazepines. Finally, respectively. Among energy parameters, heat of formation
a two-component PLS model based on 10 original descriptors (Heat.Form) exerted the most important contribution to the
was obtained with N ¼ 9, R 2 ¼ 0.95, Q 2 ¼ 0.87, RMSEE ¼ 0.29. model with a negative sign, while electronic, nuclear and binding
In Table II, the observed and predicted PMR values, as well as energy (Eelectr, Enuclear and Ebinding) showed moderate influence.
the matching residuals, are included. The basicity character (B) of compounds contributed consider-
ably to the model with a positive sign, followed by lipophilicity
expressed as ClogP, which exerted negative influence. Among
Table II the structural descriptors, nNr and nN were the most important
Observed PMR Data Taken from the Literature (22), Predicted PMR Data by QSAR Modeling and the
with a negative sign, following nC¼C that exerted positive influ-
Matching Residuals for the Chemical Class of Tricyclic Antidepressants (RMSEE ¼ 0.29)
ence to the model. Flexibility expressed by nRB also contributed
Compounds PMRobs PMRpred PMRobs 2 PMRpred to the model with negative impact.
Amitriptyline 3.1 2.7 0.4 Validation procedure using the permutation test showed that
Clomipramine 1.9 1.9 0.0 R 2 and Q 2 presented intercepts close (0.0, 0.422) and below (0.0,
Cyclobenzaprine 2.2 2.2 0.0
Desipramine 2.4 2.0 0.4 20.222) zero, respectively, indicating robustness of the model.
Dothiepin 3.0 2.7 0.3 Moreover, no significant model was obtained (R2 , 0.2, Q2 , 0.1),
Doxepin 5.5 5.3 0.2 when the entire model development procedure for the nine
Imipramine 1.9 2.1 20.2
Maprotiline 4.7 (2.3) (2.4) compounds was repeated with randomized response data (26).
Nortriptyline 2.4 2.6 20.2 For external validation, the same three-component PLS model
Trimipramine 1.6 1.5 0.1
was obtained for the training (n ¼ 7) set each time and success-
Predicted PMR data and the matching residual for maprotiline, which was identified as an outlier, are ful PMR predictions (0.21 , RMSEP , 0.40) were provided for
depicted into brackets. the corresponding test set (N ¼ 2).

Figure 2. Histograms of (A) VIPs and (B) coefficients of the original descriptors used in the final PLS models for tricyclic antidepressants. Heat.Form, heat of formation; B, hydrogen
bond basicity; ClogP, calculated octanol–water partition coefficient by Biobyte 4.0; nN, total number of nitrogen; nNr, number of nitrogen into rings; nC¼C, number of double bonds;
nRB, number of rotatable bonds; Eelectr, electronic energy; Enuclear, nuclear energy; Ebinding, binding energy.

QSAR Analysis in Forensic Toxicology 245

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 Discussion
Currently, QSAR methodology has widely been accepted to
evaluate and predict Absorption, Distribution, Metabolism,
Excretion/Toxicity (ADME/Tox) processes, such as passive bio-
membrane permeation (27). Since PMR process includes passive
diffusion through biomembranes as an essential step among
others, it could be considered as an ADME endpoint with
enhanced chance to effectively be predicted by QSAR method-
ology. In this context, we previously applied QSAR methodology
for modeling PMR data using a data set of structurally heteroge-
neous drugs (25). The derived QSAR model provided an inform-
ative illustration of the contributing molecular, physicochemical
and structural properties of drugs in the PMR process. However,
it presented low predictability (R 2 ¼ 0.65, Q 2 ¼ 0.56, RMSEE ¼
0.34) and limited applicability, since for a significant number of
drugs (N ¼ 18, 23%) no accurate predictions were obtained (25).
In view of above consideration, the present study aimed to de-
velop more specific QSAR models using structurally homoge-
neous data sets, highlighting to the contribution of specific
structural characteristics of distinct chemical classes in the
PMR process.
We selected two major chemical classes of drugs, benzodiaze-
pines and tricyclic antidepressants, for which a sufficient num-
ber of PMR data exist in the literature compared with other
chemicals classes. These highly prescribed drugs are frequently
used together with legal or illegal drugs and can result in synergy
of symptoms and intoxication (5, 7, 8, 28, 29). Thus, the estima-
tion of their PMR is of great interest in the field of forensic toxi-
cology in order to avoid potential complications concerning the
interpretation of their analytical results determined in a toxico-
logical laboratory (30, 31).
In the present study, QSAR methodology was efficiently
applied for modeling PMR data of both data sets. The derived
QSAR models were characterized by a reasonable improved
statistical fit compared with the previously reported model on
structurally diverse drugs (25). For both chemical classes, the
basic functionalities of compounds exerted positive influence
on PMR. Thus, the positive contribution of the basicity charac-
ter in the PMR process seems to be a common feature inde-
pendently of the specific structural domain of each chemical
class, as we previously identified descriptors related to the
basic functionalities of compounds as the most important in
the ‘global’ QSAR model (25). In this context, several studies
have documented that when bodies are in a supine position;
drugs with basic functionalities rapidly diffuse from lungs
into the left heart compartments through the pulmonary
venous blood rather than simply diffuse across concentration
gradients (32 – 34). It was also shown that basic drugs, including
tricyclic antidepressants, can bind selectively to the myo-
cardium and that drug diffusion from the myocardium into
heart blood may, in turn, result in enhanced heart blood
concentrations (22). In this aspect, it should be noted that,
for tricyclic antidepressants, the derived model was character-
ized by slightly inferior statistics compared with that for benzo-
diazepines. This may be attributed to the fact that the tricyclic
antidepressants under study exert stronger basic functionalities
( pKabasic  9.1) compared with benzodiazepines ( pKabasic 
7.4), which may increase the complexity of their PMR process
246 Giaginis et al.
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by binding at a higher extent to the myocardium, rendering the
determination of C : P ratio more sensitive to experimental
errors.
The derived QSAR models presented considerable differences
concerning the other contributing molecular, physicochemical
and structural properties of drugs in the PMR process. For
benzodiazepine chemical class, energy parameters, and espe-
cially the reactivity (ELUMO – EHOMO) of compounds, as well as
molecular size parameters (Refr, Pol, SAVol and SASA) exerted
considerable influence on PMR process with a negative sign.
For tricyclic antidepressants, heat of formation (Heat.Form),
lipophilicity (ClogP), structural characteristics (nN and nNr)
and flexibility (nRB) exerted the most important influence on
PMR process with negative impact. Notably, flunitrazepam,
midazolam and triazolam that were identified as outliers in the
previously reported ‘global’ QSAR model were successfully pre-
dicted in the structural specific model for benzodiazepines
(25). Accordingly, three outliers of the ‘global’ QSAR model, clo-
mipramine, doxepin and trimipramine were effectively treated
in the structurally specific model for tricyclic antidepressants
(25). On the other hand, maprotiline was identified as an ex-
treme outlier in both global and structurally specific QSAR mod-
els, with predicted C : P values 2.5 and 2.3, respectively, which
strongly deviate from that referred to the literature (25). The
underestimated predicted C : P value may be ascribed to ill-
defined literature experimental measurements or to other pro-
cess occurring during postmortem period beyond passive diffu-
sion; e.g., biotransformation of maprotiline by metabolizing
enzymes. In the later case, the currently applied QSAR method-
ology does not generally account explicitly since it cannot take
into consideration potential drug metabolism process.
Collectively, the above-mentioned comparisons amplify that
QSAR analysis could be considered as a potential complemen-
tary tool to validate experimental data with certain, however,
serious limitations.
Alarmingly enough, the complexity, subtlety and sometimes
ill-defined nature of PMR endpoints combined with the lack of
reliable available data constitute major drawbacks for the devel-
opment of computational classification and prediction models in
the area of forensic toxicology. PMR data are currently being
derived by case reports, which undoubtedly are characterized
by low accuracy and reproducibility (30, 31). It should also be
taken into consideration the fact that although there is good evi-
dence that C : P ratio is related to PMR, it cannot be assumed that
the peripheral blood drug concentration is equal to the ante-
mortem concentration (24). Moreover, it should be kept on
mind that C : P ratio is expected to be higher in case of acute poi-
soning compared with cases of chronic exposure. The collec-
tion of autopsy samples from either a heart chamber or the
pericardial sac may also result in drug concentration measure-
ments that are significantly higher than the peripheral concen-
trations, leading to inaccurate interpretation of the analytical
results (2). In this respect, MVDA seems to be advantageous
compared with conventional statistical methods, as it permits
the use of biological data of lower accuracy and reproducibility
(18, 19). However, well-defined PMR data derived by animal
studies, where experimental conditions are more reproducible,
constitute an emergent demand in order for QSAR models of
 higher accuracy to be obtained. In a congeneric set of three
b-blockers, atenolol, metoprolol and propranolol, lipophilicity
was found to influence their PMR in rabbit in a certain number
of anatomical sites, such as the stomach, the lungs, the cardiac
muscle, the cardiac blood or the liver, whereas it did not appear
to intervene in other sites, such as brain and vitreous humor
(34). Such experimental PMR data deserve special attention
and should be extended to a larger number of structurally
related compounds in order to be analyzed by QSAR
methodology.
In conclusion, QSAR analysis was efficiently applied for mod-
eling PMR data of structurally specific chemical classes, such as
benzodiazepines and tricyclic antidepressants, which attract
considerable interest in the field of forensic toxicology. The
derived QSAR models could be used as a complementary tool
to provide an informative illustration of the contributing mo-
lecular, physicochemical and structural properties of drugs in
the PMR process. However, it should be noted that the com-
plexity, subtlety and ill-defined nature of PMR data, as well as
the time-dependent and non-static character of this process,
raises serious concerns about the reliability of QSAR analysis
to predict the degree of redistribution. In this aspect, well-
defined PMR data derived by animal studies, where experimen-
tal conditions are more reproducible, constitute an emergent
demand in order to validate whether QSAR methodology
could effectively be applied in high-throughput screening pro-
cess of drug testing and analysis in the field of forensic
toxicology.
Conflict of interest
None declared.
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