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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 10, Number 9, November 2009
Contents
Recent Advances in Drug Intolerance
Guest Editor: José A.G. Agúndez
Editorial Pp.
946
Metabolomics in Drug Intolerance Pp. 947-955
I. Andreu, C. Mayorga and M.A. Miranda
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Article]
Pharmacogenomics in Drug Induced Liver Injury Pp.
956-970
R.J. Andrade, J.A.G. Agúndez, M.I. Lucena, C. Martínez,
R. Cueto and E. García-Martín
[Abstract] [Purchase
Article]
Hypersensitivity Reactions to Non-Steroidal Anti-Inflammatory
Drugs Pp. 971-980
J.A. Cornejo-Garcia, N. Blanca-López, I. Doña,
I. Andreu, J.A.G. Agúndez, M. Carballo, M. Blanca and
M.G. Canto
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Article]
On Therapeutic Drug Monitoring of Thiopurines in Inflammatory
Bowel Disease; Pharmacology, Pharmacogenomics, Drug Intolerance
and Clinical Relevance Pp. 981-997
D.P. van Asseldonk, N.K.H. de Boer, G.J. Peters, A.I.
Veldkamp, C.J. Mulder and Ad. A. van Bodegraven
[Abstract] [Purchase
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Pharmacogenomics in Aspirin Intolerance Pp. 998-1008
J.A.G. Agúndez, C. Martínez, D. Pérez-Sala,
M. Carballo, M.J. Torres and E. García-Martín
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General Articles
Human CYP2C8: Structure, Substrate Specificity, Inhibitor
Selectivity, Inducers and Polymorphisms Pp. 1009-1047
X.-S. Lai, L.-P. Yang, X.-T. Li, J.-P. Liu, Z.-W. Zhou
and S.-F. Zhou
[Abstract] [Purchase
Article]
Enzymatic Biotransformation of Synthetic Dyes Pp.
1048-1054
S. Rodríguez-Couto
[Abstract]
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Article]
St. John's Wort Components and the Brain: Uptake,
Concentrations Reached and the Mechanisms Underlying Pharmacological
Effects Pp. 1055-1065
S. Caccia and M. Gobbi
[Abstract]
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Article]
Abstracts
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Editorial
Drug intolerance constitutes an important cause of
patient morbidity and mortality. Intolerance events can be
detected at the final stages of drug development, during clinical
trials or even after drug approval. Besides the risks derived
from their clinical outcome, drug intolerance events may result
in stopping drugs for further development, restriction of
drug use or drug withdrawal from the market, in spite of the
fact that many of the drugs causing intolerance are safe and
efficient for most patients. For this reason, the identification
of the mechanisms involved in drug intolerance and the early
detection of at-risk individuals are key issues. Examples
for severe drug intolerance events include among others hepatotoxicity,
which ranges from sub-clinical elevations in liver enzyme
concentrations to acute liver failure with a mean mortality
of 10% for jaundiced patients with acute toxic hepatocellular
damage [1]. Acute gastrointestinal bleeding is another common
adverse effect, especially for non-steroidal antiinflammatory
drugs, with a mortality rate between 7 and 11% [2]; and hypersensitivity
reactions, including anaphylaxis, are also commonly caused
by non-steroidal antiinflammatory drugs [3]. Besides licensed
drugs, herbal and natural supplements are recognized as causing
intolerance events with increasing frequency as patients turn
more and more to alternative medicine [4].
The mechanisms underlying the interindividual variability
in the susceptibility to drug intolerance are poorly understood.
In recent years growing evidence points to a genetic basis
for such susceptibility, either related to drug bioactivation
or biodisposition, to variability in drug targets such as
enzymes, transporters or receptors, as well as to genetic
variability in general signaling and detoxication mechanisms
[5-10]. Although studies are in progress, with few exceptions
there is a paucity of published data on the relationship between
genetic polymorphisms and drug intolerance. In addition, recent
evidence suggests that pharmacogenomic studies are insufficient
to predict adverse drug reactions [8] and that the combination
of pharmacogenomic and metabolomics studies may be far more
informative [11].
This special issue of Current Drug Metabolism on drug intolerance
provides a collection of review articles covering basic and
clinical topics related to drug intolerance, and identifies
further aspects that should be investigated in detail. The
paper by Andreu and coworkers discusses the potential role
of metabolomics in drug intolerance. Hopefully the combination
of metabolomics with pharmacogenomics will give essential
information to identify at-risk subjects and to clarify the
mechanisms related to bioactivation in drug intolerance. Two
papers discuss major drug intolerance mechanisms. These include
drug-induced liver injury in a review by Andrade and coworkers,
and hypersensitivity reactions in a review by Cornejo and
colleagues. These two review papers include clinical and diagnostic
criteria as well as an update of causal mechanisms including
genetic and non-genetic risk factors. Finally, two review
papers exemplify aspects on drug intolerance. The paper by
Van Asseldonk et al. discusses therapeutic drug monitoring,
pharmacogenomics and drug intolerance of thiopurines, and
the paper by Agúndez and coworkers discusses basic
and clinical aspects on the mechanisms involved in aspirin
intolerance, including gastrointestinal complications and
hypersensitivity.
Further advances in drug intolerance research can be expected
with the combined information obtained from proteomics, genomics,
metabolomics, bioinformatics, immunology, toxicology and pharmacology.
We hope that in the next few years the research effort dedicated
to these studies will result in widely used tools capable
of increasing the efficiency and safety of drug therapy, and/or
to identify individuals with increased susceptibility to develop
drug intolerance events. Hopefully, this information will
also be useful to recover drugs that have been withdrawn from
the market, for selective use in non-susceptible patients.
I would like to thank, as Guest Editor of the special issue
of Current Drug Metabolism, all the authors who kindly contributed
to this issue and to our reviewers.
REFERENCES
[1] Zimmerman, H. J. Hepatotoxicity. The adverse effects of
drugs and other chemicals in the liver. 2nd
ed. 1999, Philadelphia: Lippincott Williams
& Wilkins.
[2] Straube, S.; Tramer, M. R.; Moore, R. A.; Derry, S.; McQuay,
H. J. Mortality with upper gastrointestinal bleeding and perforation:
effects of time and NSAID use. BMC Gastroenterol.,
2009, 9( 41).
[3] van der Klauw, M. M.; Wilson, J. H.; Stricker, B. H. Drug-associated
anaphylaxis: 20 years of reporting in The Netherlands (1974-1994)
and review of the literature. Clin. Exp. Allergy,
1996, 26(12), 1355-1363.
[4] Gunawan, B.; Kaplowitz, N. Clinical perspectives on xenobiotic-induced
hepatotoxicity. Drug Metab. Rev., 2004,
36(2), 301-312.
[5] Lucena, M. I.; Andrade, R. J.; Martinez, C.; Ulzurrun,
E.; Garcia-Martin, E.; Borraz, Y.; Fernandez, M. C.; Romero-Gomez,
M.; Castiella, A.; Planas, R.; Costa, J.; Anzola, S.; Agundez,
J. A. Glutathione S-transferase m1 and t1 null genotypes increase
susceptibility to idiosyncratic drug-induced liver injury.
Hepatology, 2008, 48(2),
588-596.
[6] Blanco, G.; Martinez, C.; Ladero, J. M.; Garcia-Martin,
E.; Taxonera, C.; Gamito, F. G.; Diaz-Rubio, M.; Agundez,
J. A. Interaction of CYP2C8 and CYP2C9 genotypes modifies
the risk for nonsteroidal anti-inflammatory drugs-related
acute gastrointestinal bleeding. Pharmacogenet. Genomics,
2008, 18(1), 37-43.
[7] Garcia-Martin, E.; Ayuso, P.; Martinez, C.; Blanca, M.;
Agundez, J. A. Histamine pharmacogenomics. Pharmacogenomics,
2009, 10(5), 867-883.
[8] Palmieri, O.; Latiano, A.; Bossa, F.; Vecchi, M.; D'Inca,
R.; Guagnozzi, D.; Tonelli, F.; Cucchiara, S.; Valvano, M.
R.; Latiano, T.; Andriulli, A.; Annese, V. Sequential evaluation
of thiopurine methyltransferase, inosine triphosphate pyrophosphatase,
and HPRT1 genes polymorphisms to explain thiopurines' toxicity
and efficacy. Aliment. Pharmacol. Ther., 2007,
26(5), 737-745.
[9] Kim, S. H.; Yang, E. M.; Lee, H. N.; Cho, B. Y.; Ye, Y.
M.; Park, H. S. Combined effect of IL-10 and TGF-beta1 promoter
polymorphisms as a risk factor for aspirin-intolerant asthma
and rhinosinusitis. Allergy, 2009,
64(8), 1221-1225.
[10] Choi, J. H.; Kim, S. H.; Cho, B. Y.; Lee, S. K.; Kim,
S. H.; Suh, C. H.; Park, H. S. Association of TNF-alpha promoter
polymorphisms with aspirin-induced urticaria. J. Clin.
Pharm. Ther., 2009, 34(2),
231-238.
[11] Agundez, J. A.; Garcia-Martin, E.; Martinez, C. Genetically
based impairment in CYP2C8- and CYP2C9-dependent NSAID metabolism
as a risk factor for gastrointestinal bleeding: is a combination
of pharmacogenomics and metabolomics required to improve personalized
medicine? Expert. Opin. Drug Metab. Toxicol., 2009,
5(6), 607-620.
José A.G. Agúndez
Guest Editor
Current Drug Metabolism
Department of Pharmacology, Medical School
University of Extremadura
Avda. de Elvas s/n, E-06071, Badajoz
Spain
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Metabolomics in Drug Intolerance
I. Andreu, C. Mayorga and M.A. Miranda
Adverse drug reactions appear during the clinical
use of a drug and constitute a health problem, as they are
an important cause of patient morbidity and mortality. In
addition, they constitute a major drawback for drug development.
Intolerance processes occurring after administration of low
drug doses are known as idiosyncratic reactions or as hypersensitivity
reactions; the most commonly accepted mechanism for immunological
activation is the hapten hypothesis. Most drugs are not reactive
per se towards proteins, hence in a number of cases bioactivation
seems to be a prerequisite for adduct formation and the subsequent
hypersensitivity reaction. Although biotransformation is normally
associated with a decreased toxicity, metabolites are sometimes
more toxic and reactive than the parent drug. Drug metabolizing
enzymes develop their activities especially in liver, where
reactive metabolites bind to proteins inducing hepatotoxicity,
whereas in skin keratinocytes exhibit the highest biotransformation
capability. In the present review, some specific examples
of the toxicological consequences of drug biotransformation
are given. They include nimesulide, metamizol, celecoxib,
paracetamol, dapsone, sulfamethoxazole, amodiaquine, nevirapine,
troglitazone, zileuton, felbamate, panadiplon, benzbromarone,
fipexide and flutamide. In general, these examples are taken
from the recent scientific literature, mostly published during
the last decade.
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Pharmacogenomics in Drug Induced Liver Injury
R.J. Andrade, J.A.G. Agúndez, M.I. Lucena, C. Martínez,
R. Cueto and E. García-Martín
Drug-induced liver injury (DILI) is a severe adverse
effect. The majority of DILI cases are idiosyncratic and several
mecha-nisms have been postulated to explain why some subjects
develop DILI with drugs that are safe for the majority of
individuals. Major mechanisms proposed for DILI are based
on the production of reactive metabolites, immune-mediated
hepatotoxicity, a “danger signal” hypothesis and/or
alterations in mitochondrial function. These mechanisms are
compatible with the hypothesis for genetic variability in
drug metabolism or bioactivation and are a major determinant
for DILI. In this review we summarize present knowledge on
underlying mechanisms, and clinical expression as well as
genetic and non-genetic factors that modulate the risk of
developing DILI. With regard to DILI pharmacogenomics, we
summarize current evidence on the role of polymorphisms in
genes coding for the drug-metabolizing enzymes CYP1A2, CYP2C9,
CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, NAT2, GSTM1, GSTT1,
UGT1A1, UGT1A3, UGT1A9 and UGT2B7. Conclusive evidence for
association with DILI risk has been obtained for non-mutated
CYP2E1, slow NAT2 and slow GSTM1
genotypes. For the rest of the genes additional pharmacogenomics
and toxicogenomics studies are required. We identify potential
sources of heterogeneity in studies carried out so far as
well as new genetic targets which require further investigation.
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Hypersensitivity Reactions to Non-Steroidal Anti-Inflammatory
Drugs
J.A. Cornejo-Garcia, N. Blanca-López, I. Doña,
I. Andreu, J.A.G. Agúndez, M. Carballo, M. Blanca and
M.G. Canto
NSAIDs are the most important group of drugs involved
in hypersensitivity drug reactions, and include heterogeneous
compounds with very different chemical structures. These reactions
can be IgE dependent (immediate reactions), T cell-mediated
(non-immediate), or induced by a non-specific immunological
mechanism related with the blocking of the COX-1 enzyme and
the shunting to the lipooxygenase pathway (cross-intolerant
reactions).
Cutaneous symptoms are the most frequent, with ibuprofen,
naproxen and diclofenac being common culprit drugs worldwide,
although others can be involved because patterns of consumption
and exposure rates vary between countries. A very important
proportion of immunological reactions are immediate, with
urticaria and anaphylaxis being the typical clinical manifestations.
Non-immediate reactions comprise a number of heterogeneous
entities ranging from mild exanthema to severe TEN or DRESS
syndrome, as well as organ-specific reactions such as hepatitis
or pneumonitis. Cross-intolerant reactions appear to non-chemically
related drugs, and involve respiratory airways, skin or both.
In vivo diagnostic tests are based on the capacity
of the skin to respond to the culprit drug, but their sensitivity
is in many instances rather low. The approach for in vitro
testing consists of either detecting specific IgE antibodies
or studying the proliferation of T lymphocytes toward the
eliciting drug. No appropriate tests are yet available for
the in vitro validation of cross-intolerance reactions,
although techniques based on the stimulation of basophils
have been proposed. Based on these findings, the diagnostic
approach is often based on the controlled administration of
the drug to assess tolerance.
In this work we review current knowledge on hypersensitivity
reactions to NSAIDs, including diagnostic approach and genetic
studies.
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On Therapeutic Drug Monitoring of Thiopurines in Inflammatory
Bowel Disease; Pharmacology, Pharmacogenomics, Drug Intolerance
and Clinical Relevance
D.P. van Asseldonk, N.K.H. de Boer, G.J. Peters, A.I.
Veldkamp, C.J. Mulder and Ad. A. van Bodegraven
Thiopurines such as azathioprine, 6-mercaptopurine and
6-thioguanine are antimetabolites that have been used for
several decades in the treatment of several diseases including
inflammatory bowel diseases. Additional anti-inflammatory
properties of these thiopurines have been discovered in recent
years. Thiopurine metabolism is complex due to the involvement
of multiple enzymes, of which the activities are genetically
determined and cell type dependent. Single nucleotide polymorphisms
in the genes encoding these enzymes have been correlated with
altered activities and drug intolerance. Detailed implications
of these will be reviewed. Over the years several methods
of therapeutic drug monitoring have been developed in an attempt
to relate thiopurine drug availability with efficacy and intolerance.
In this respect, monitoring pharmacologically active 6-thioguanine
nucleotide concentrations is most widely used. So far, however,
the clinical usefulness of these methods is hampered by methodological
limitations. Some drug interactions may optimize the metabolization
of thiopurines and consequently increase its efficacy and
decrease drug intolerance. This review focuses on the clinical
relevance and usefulness of therapeutic drug monitoring of
thiopurines and provides suggestions to optimize thiopurine
therapy in the treatment of inflammatory bowel diseases.
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Pharmacogenomics in Aspirin Intolerance
J.A.G. Agúndez, C. Martínez, D. Pérez-Sala,
M. Carballo, M.J. Torres and E. García-Martín
Polymorphisms in drug-related enzymes and receptors are
often strongly related to altered drug response and to the
risk of developing drug intolerance. Aspirin, usually available
as an over-the-counter drug, is one of the most used drugs
worldwide and is a common cause of drug intolerance events.
Aspirin undergoes polymorphic metabolism. Among the enzymes
involved in aspirin biodisposition a major role is played
by the enzymes UDP-glucuronosyltransferase UGT1A6, cytochrome
P450 CYP2C9 and the xenobiotic/medium chain fatty acid:CoA
ligase ACSM2, although other UGTs and ACSMs enzymes may significantly
contribute to aspirin metabolism. UGT1A6, CYP2C9 and ACSM2
are polymorphic, as well as PTGS1 and PTGS2, the genes coding
for the enzymes cyclo-oxygenases COX1 and COX2, respectively.
The present review analyzes the importance of genetic variations
in enzymes involved in the metabolism and in the effects of
aspirin and common polymorphisms related to aspirin intolerance,
and it raises hypotheses on genetic factors related to altered
response to aspirin that require further investigation. Major
polymorphisms related to aspirin biodisposition are rs2070959,
rs1105879 and rs6759892 for the UGT1A6 gene, rs1133607
for the ACSM2 gene, and rs1799853, rs1057910, rs28371686,
rs9332131 and rs28371685 for the CYP2C9 gene. Regarding
aspirin effects, major PGTS1 targets are rs3842787
and rs5789 for European subjects, and rs3842789 and rs3842792
for African subjects. For the PTGS2 gene nonsynonymous
SNPs are likely to be of low relevance because of the influence
of transcriptional and posttranscriptional factors. Combined
studies for the above mentioned polymorphisms and those corresponding
to other genes related to aspirin intolerance will provide
excellent tools to identify individuals with a high risk to
develop intolerance to aspirin.
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Human CYP2C8: Structure, Substrate Specificity, Inhibitor
Selectivity, Inducers and Polymorphisms
X.-S. Lai, L.-P. Yang, X.-T. Li, J.-P. Liu, Z.-W. Zhou
and S.-F. Zhou
Human CYP2C8 is a key member of the CYP2C family
and metabolizes more than 60 clinical drugs. A number of active
site residues in CYP2C8 have been identified based on homology
modeling and site-directed mutagenesis studies. In the structure
of CYP2C8, the large active site cavity exhibits a trifurcated
topology that approximates a T or Y shape, which is consistent
with the finding that CYP2C8 can efficiently oxidize relatively
large substrates such as paclitaxel and cerivastatin. The
active site cavity of CYP2C8 contains at least 48 amino acid
residues and many of them are important for substrate binding.
The structures of CYP2C8 in complex with distinct ligands
have revealed that the enzyme can bind divergent substrates
and inhibitors without extensive conformational changes. CYP2C8
is a major catalyst in the metabolism of paclitaxel, amodiaquine,
troglitazone, amiodarone, verapamil and ibuprofen, with a
secondary role in the biotransformation of cerivastatin and
fluvastatin. CYP2C8 also metabolises endogenous compounds
such as retinoids and arachidonic acid. Many drugs are inhibitors
of CYP2C8 and inhibition of this enzyme may result in clinical
drug interactions. The pregnane X receptor, constitutive androstane
receptor, and glucocorticoid receptor are likely to involve
the regulation of CYP2C8. A number of genetic mutations
in the CYP2C 8 gene have been identified in humans
and some of them have functional impact on the clearance of
drugs. Further studies are needed to delineate the role of
CYP2C8 in drug development and clinical practice.
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Enzymatic Biotransformation of Synthetic Dyes
S. Rodríguez-Couto
Environmental pollution by discharge of dye-containing effluents
represents a serious ecological concern in many countries.
Public demands for colour-free discharges to receiving waters
have made decolouration of a variety of industrial wastewater
a top priority. The current existing techniques for dye removal
have several drawbacks such as high cost, low efficiency,
use of large amounts of chemicals and formation of toxic sub-products.
This has impelled the search for alternative methods such
as those based on oxidative enzymes. This approach is believed
to be a promising technology since it is cost-effective, environmentally
friendly and does not produce sludge. Enzymatic transformation
of synthetic dyes can be described as the conversion of dye
molecules by enzymes into simpler and generally colourless
molecules. Detailed characterisation of the metabolites produced
during enzymatic transformation of synthetic dyes as well
as ecotoxicity studies is of great importance to assess the
effectiveness of the biodegradation process. However, most
reports on the biotreatment of dyes mainly deal with decolouration
and there are few reports on the reduction in toxicity or
on the identification of the biodegradation products. This
implies a limitation to assess their true technical potential.
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St. John's Wort Components and the Brain: Uptake,
Concentrations Reached and the Mechanisms Underlying Pharmacological
Effects
S. Caccia and M. Gobbi
Hypericum perforatum L. (St. John’s wort) extracts
have gained popularity as an alternative to conventional antidepressant
drugs for mild to moderate forms of depressive disorders.
New potential psychiatric uses for extracts in obsessive-compulsive
disorder, generalised anxiety disorder and alcohol dependence
have also been suggested on the basis of animal studies. The
neurochemical mechanisms of these central actions are still
debated but several components have antidepressant-like and
anxiolytic-like effects in animals, or interact with neurotransmitter
systems believed to be causally involved in depression, anxiety
and in psychiatric illness generally. However, these data
should interpreted taking account of the pharmacokinetic data
on the main components, particularly those of their brain
distribution and concentrations and the relationships with
blood concentrations; the (scant) data so far suggest that
the acylphloroglucinol hyperforin, the flavonol quercetin
and its glycosylated forms and their metabolites, the biflavones
amentoflavone and its I3,II8-analog biapigenin and the naphthodianthrones
hypericin and pseudohypericin pass the blood-brain barrier
poorly in animals. The brain concentrations of all these high-molecular
weight, poorly water-soluble compounds after pharmacologically
effective doses of the extracts are therefore far below those
effective on neurotransmitter receptors and the mechanisms
which are obviously important in the central effects of conventional,
pharmacologically related drugs. Additional pharmacokinetic
data on the brain concentrations of these and other constituents
and their metabolites are therefore required for a more meaningful
interpretation of the central effects of St. John’s
Wort extracts.
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