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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 8, Number 8, December 2007
Contents
Periodontal Diseases and Rheumatoid Arthritis: A Coincident
Model for Therapeutic Intervention?
M. Soory
[Abstract]
Xenobiotic Metabolism in Human Skin and 3D Human Skin
Reconstructs: A Review Pp. 758-772
S. Gibbs, J.J.M. van de Sandt, H.F. Merk, D.J. Lockley,
R.U. Pendlington and C.K. Pease
[Abstract]
In Vitro Monitoring Chlorogenic Acid in Human
Urine and Serum by a Flow Injection System Exploiting the
Luminol-Dissolved Oxygen Chemiluminescence Reaction
Pp. 773-777
X. Xie, X. He, X. Qiu and Z. Song
[Abstract]
A Pharmacogenetic Study of Pregnane X Receptor (NR1I2)
in Han Chinese Pp. 778-786
X.-D. Wang, J.-L. Li, Q.-B. Su, X.-Y. Deng, Y. Lu, J.
Chen, J.-X. Zhang, L.-Z. Zhao, Z. Zuo, E. Chan, X. Chen, B.
Chowbay, C.C. Xue, M. Huang and S.-F. Zhou
[Abstract]
Multidrug Resistance Associated Proteins as Determining
Factors of Pharmacokinetics and Pharmacodynamics of Drugs
Pp. 787-802
X.-Q. Yu, C.C. Xue, G. Wang and S.-F. Zhou
[Abstract]
Cholinesterase Reactivators: The Fate and Effects
in the Organism Poisoned with Organophosphates/Nerve Agents
Pp. 803-809
J. Bajgar, K. Kuca, D. Jun, L. Bartosova and J. Fusek
[Abstract]
Quantitative Correlations Among CYP3A Sensitive Substrates
and Inhibitors: Literature Analysis Pp. 810-814
I. Ragueneau-Majlessi, X. Boulenc, C. Rauch, H. Hachad
and R.H. Levy
[Abstract]
The Conduct of Drug Metabolism Studies Considered
Good Practice (I): Analytical Systems and In Vivo
Studies Pp. 815-821
X. Liu and L. Jia
[Abstract]
The Conduct of Drug Metabolism Studies Considered
Good Practice (II): In Vitro Experiments
Pp. 822-829
L. Jia and X. Liu
[Abstract]
Interactions of Polyphenolic Compounds with Drug Disposition
and Metabolism Pp. 830-838
F. Galli
[Abstract]
Isoniazid: Metabolic Aspects and Toxicological Correlates
Pp. 839-851
P. Preziosi
[Abstract]
Abstracts
[Back to top]
Periodontal Diseases and Rheumatoid Arthritis:
A Coincident Model for Therapeutic Intervention?
M. Soory
There are remarkable similarities in the pathogenesis of periodontal
diseases and rheumatoid arthritis. The mechanisms that drive
antigen induced sequelae of oxidative stress are discussed
in this review. A poorly modulated inflammatory response drives
both diseases resulting in oxidative stress induced tissue
injury. Immune complex formation in response to the periodontal
pathogen Porphyromonas gingivalis triggering the
production of ROS in both gingivae and synovium of RA patients
has been reported. Elevated antibody levels to several periodontal
pathogens in RA patients has implications on both RA and periodontal
diseases. Periodontal patients are challenged individuals
representing a multifactorial aetiopathogenesis with potential
for therapeutic intervention in the context of free radical
damage. Subjects with moderate to severe periodontal bone
loss are significantly more likely than healthy individuals
to have several co-existing systemic conditions resulting
in ROS mediated damage. There is potential for dual induction
of periodontal disease by existing inflammatory mechanisms
of systemic diseases rather than exacerbation of low grade
inflammation only; emphasizing the relevance of reducing inflammatory
burden for disease control. Therapeutic strategies based on
disease mechanisms include combined low dose non-steroidal
anti-inflammatory drugs and doxycycline for synergistic reduction
of matrix metalloproteinase activity in periodontal tissues
and RA; sub-optimal dosing with CMT-8 and a biphosphonate
clodronate to reduce pathologically elevated levels of MMPs,
elastase and to restore alveolar bone in experimental periodontits
demonstrating dual applications. Therapeutic interventions
relevant to both diseases discussed in this review, have scope
for a double hit in periodontal patients with co-existing
RA and vice versa.
[Back to top]
Xenobiotic Metabolism in Human Skin and 3D Human Skin
Reconstructs: A Review
S. Gibbs, J.J.M. van de Sandt, H.F. Merk, D.J. Lockley,
R.U. Pendlington and C.K. Pease
In this review, we discuss and compare studies of xenobiotic
metabolism in both human skin and 3D human skin reconstructs.
In comparison to the liver, the skin is a less studied organ
in terms of characterising metabolic capability. While the
skin forms the major protective barrier to environmental chemical
exposure, it is also a potential target organ for adverse
health effects. Occupational, accidental or intended-use exposure
to toxic chemicals could result in acute or delayed injury
to the skin (e.g. inflammation, allergy, cancer). Skin metabolism
may play a role in the manifestation or amelioration of adverse
effects via the topical route. Today, we have robust testing
strategies to assess the potential for local skin toxicity
of chemical exposure. Such methods (e.g. the local lymph node
assay for assessing skin sensitisation; skin painting carcinogenicity
studies) incorporate skin metabolism implicitly in the in
vivo model system used. In light of recent European legislation
(i.e. 7th Amendment to the
Cosmetics Directive and Registration Evaluation and Authorisation
of existing Chemicals (REACH)), non-animal approaches will
be required to reduce and replace animal experiments for chemical
risk assessment. It is expected that new models and approaches
will need to account for skin metabolism explicitly, as the
mechanisms of adverse effects in the skin are deconvoluted.
3D skin models have been proposed as a tool to use in new
in vitro alternative approaches. In order to be able
to use 3D skin models in this context, we need to understand
their metabolic competency in relation to xenobiotic bio-transformation
and whether functional activity is representative of that
seen in human skin.
[Back to top]
In Vitro Monitoring Chlorogenic Acid in Human
Urine and Serum by a Flow Injection System Exploiting the
Luminol-Dissolved Oxygen Chemiluminescence Reaction
X. Xie, X. He, X. Qiu and Z. Song
A sensitive flow injection chemiluminescence method, based
on the inhibitory effect of chlorogenic acid on the reaction
between luminol and dissolved oxygen, was presented for the
determination of chlorogenic acid. It was found that the decrease
of chemilu-minescence intensity was linear with the logarithm
of chlorogenic acid concentration over the range from 1.0
ng•ml-1 to 100 ng•ml-1
(r2 = 0.9978), with the detection limit of 0.3 ng•ml-1
(3σ).
At the flow rate of 2.0 ml•min-1
for each line, a complete analytical process could be performed
within 0.5 min, including sampling and washing, with a relative
standard deviation lower than 3.0% (n = 5). The proposed procedure
was applied successfully to determine chlorogenic acid in
Flo Lonicerae for different drawn time and monitor the excretion
of chlorogenic acid in human urine. It was found that the
excretive amounts of chlorogenic acid in urine reached its
maximum in 2 hours after intake of Flo Lonicerae tea, presenting
an excretive ratio of 63.82% in 6 hours. With urinary excretion
rate method, the total elimination rate constant k
and half-life time t1/2
of chlorogenic acid was calculated, which were 0.7667 and
0.91 hours, respectively.
[Back to top]
A Pharmacogenetic Study of Pregnane X Receptor (NR1I2)
in Han Chinese
X.-D. Wang, J.-L. Li, Q.-B. Su, X.-Y. Deng, Y. Lu, J.
Chen, J.-X. Zhang, L.-Z. Zhao, Z. Zuo, E. Chan, X. Chen, B.
Chowbay, C.C. Xue, M. Huang and S.-F. Zhou
The pregnane X receptor (PXR/NR1I2) gene is a critical
transcriptional regulator of a number of important drug metabolizing
enzymes and transporters. This study was undertaken to determine
the frequencies of single nucleotide polymorphisms (SNPs)
and haplotypes and to detect yet unknown SNPs in the NR1I2
gene in 210 unrelated healthy Han Chinese in comparison with
other ethnic groups. We also characterized the functional
impact of two SNPs, -24622A>T in the 5’-untranslated
region and -24446C>A in exon 1 of NR1I2, by constructing
three recombinants and monitoring promoter activity using
the dual luciferase reporter gene assay. Genomic DNA was isolated
from peripheral leukocytes and subjected to polymerase chain
reaction (PCR) amplification, followed by direct DNA sequencing.
Sixteen SNPs in NR1I2 with frequencies of 0.3-90.3%
were found in Han Chinese, two of which (-25439A>G in the
5’-untranslated region and 7637C>T in intron 5) are
previously unknown. The mutant allelic frequencies varied
from 0.3% to 90.3%. Most of the detected SNPs were located
in introns. A total of 15 linkage disequilibriums were detected;
and positive linkage disequilibriums were found between -24381A>C
in exon 1 and -24113G>A in intron 1, and 252A>G in intron
2 and 275A>G in intron 2 (ρ2
= 1, P<0.001). A total of 42 haplotypes were inferred
and the two most frequent haplotypes were H1 (TCAGGGGCCACC)
and H2 (CCGAAAACTAAT) with a frequency of 15.1%. The activity
of the recombinants with alleles containing the -24622A>T
in the 5’-untranslated region or -24446C>A in exon
1 was 30-40% higher than that in the wild-type (reference
genotype). These results indicate that there are marked ethnic
differences in the frequency between Han Chinese and other
ethnic groups and that alleles with -24622A>T in the 5’-untranslated
region and -24446C>A in exon 1 of the NR1I2 gene
result in an increased activity compared to the wild-type.
Further studies are warranted to explore the clinical and
toxicological impact of SNPs and haplotypes of NR1I2
in various ethnic groups.
[Back to top]
Multidrug Resistance Associated Proteins as Determining
Factors of Pharmacokinetics and Pharmacodynamics of Drugs
X.-Q. Yu, C.C. Xue, G. Wang and S.-F. Zhou
The multidrug resistance associated proteins (MRP1, MRP2,
MRP3, MRP4, MRP5, MRP6, MRP7, MRP8 and MRP9) belong to the
ATP-binding cassette superfamily (ABCC family) of transporters.
They are expressed differentially in the liver, kidney, intestine,
brain and other tissues. These transporters are localized
to the apical and/or basolateral membrane of the hepatocytes,
enterocytes, renal proximal tubule cells and endothelial cells
of the blood-brain barrier. Several MRPs (mainly MRP1-3) are
associated with tumor resistance which is often caused by
an increased efflux and decreased intracellular accumulation
of natural product anticancer drugs and other anticancer agents.
MRPs transport a structurally diverse array of important endogenous
substances and xenobiotics and their metabolites (in particular
conjugates) with different substrate specificity and transport
kinetics. Most MRPs are subject to induction and inhibition
by a variety of compounds. Several nuclear receptors, including
pregnane X receptor (PXR), liver X receptor (LXR), and farnesoid
receptor (FXR) participate in the regulation of MRPs. MRPs
play an important role in the absorption, distribution and
elimination of various drugs in the body and thus may affect
their efficacy and toxicity and cause drug-drug interactions.
MRPs located in the blood-brain barrier can restrict the penetration
of compounds into the central nervous system. Mutation of
MRP2 causes Dubin-Johnson syndrome, while mutations
in MRP6 are responsible for pseudoxanthoma elasticum.
More recently, mutations in mouse Mrp6/Abcc6 gene
is associated with dystrophic cardiac calcification (DCC),
a disease characterized by hydroxyapatite deposition in necrotic
myocytes. A single nucleotide polymorphism, 538G>A in the
MRP8/ABCC11 gene, is responsible for determination
of earwax type. A better understanding of the function and
regulating mechanism of MRPs can help minimize and avoid drug
toxicity, unfavourable drug-drug interactions, and to over-come
drug resistance.
[Back to top]
Cholinesterase Reactivators: The Fate and Effects
in the Organism Poisoned with Organophosphates/Nerve Agents
J. Bajgar, K. Kuca, D. Jun, L. Bartosova and J. Fusek
Understanding the mechanism of action of organophosphates
(OP)/nerve agents - irreversible acetylcholinesterase (AChE,
EC 3.1.1.7) inhibition at the cholinergic synapses followed
by metabolic dysbalance of the organism - two therapeutic
principles for antidotal treatment are derived. The main drugs
are anticholinergics that antagonize the effects of accumulated
acetylcholine at the cholinergic synapses and cholinesterase
reactivators (oximes) reactivating inhibited AChE. Anticonvulsants
such as diazepam are also used to treat convulsions. Though
there are experimental data on a good therapeutic effects
of reactivators, some attempts to underestimate the role of
reactivators as effective antidotes against OP poisoning have
been made. Some arguments on the necessity of their administration
following OP poisoning are discussed. Their distribution patterns
and some metabolic and pharmacological effects are described
with the aim to resolve the question on their effective use,
possible repeated administration in the treatment of OP poisonig,
their peripheral and central effects including questions on
their penetration through the blood brain barrier as well
as a possibility to achieve their effective concentration
for AChE reactivation in the brain. Reactivation of cholinesterases
in the peripheral and central nervous system is described
and it is underlined its importance for the survival or death
of the organism poisoned with OP. Metabolization and some
other effects of oximes (not connected with AChE reactivation)
are discussed (e.g. forming of the phosphonylated oxime, parasympatholytic
action, hepatotoxicity, behavioral changes etc.). An universality
of oximes able to reactivate AChE inhibited by all OP is questioned
and therefore, needs of development of new oximes is underlined.
[Back to top]
Quantitative Correlations Among CYP3A Sensitive Substrates
and Inhibitors: Literature Analysis
I. Ragueneau-Majlessi, X. Boulenc, C. Rauch, H. Hachad
and R.H. Levy
As a follow-up to the new classification of CYP3A inhibitors,
the present work was undertaken to search for quantitative
correlations of AUC ratios between sensitive substrates and
midazolam (reference). A large set of clinical studies was
obtained utilizing the M&T Drug Interaction Database™,
and recent Product Labels. Linear relationships were found
between midazolam and four CYP3A substrates: simvastatin,
buspirone, triazolam and eplerenone. Simvastatin and buspirone
were consistently more sensitive than midazolam, independent
of the inhibitor. Quantitative correlations of AUC ratios
between four CYP3A inhibitors (fluconazole, erythromycin,
verapamil, diltiazem) and ketoconazole (400 mg/day) were also
uncovered. The average potencies of these inhibitors relative
to keto-conazole were 27% for erythromycin, 17% for fluconazole
and 19% for verapamil.
[Back to top]
The Conduct of Drug Metabolism Studies Considered
Good Practice (I): Analytical Systems and In Vivo
Studies
X. Liu and L. Jia
This review serial outlines practical and scientifically-based
approaches to conducting contemporary drug metabolism studies
considered good practice for drug development and regulatory
filing. The present part addresses analytical methods used
in the drug metabolism studies and evaluates advantages and
disadvantages of these methods as well as the related sample
preparations. The methods described here cover from conventional
radioactive labeling of drugs, which includes selection of
a proper radioisotope, its labeling position, and modern radio-pharmacokinetics
employed in microdosing by using a radionuclide to visualize
drug distribution in vivo, to currently widely-used
liquid chromatography (LC) in conjunction with mass spectrometry
(MS), tandem mass spectrometry (MS/MS), and nuclear magnetic
resonance (NMR) for quantitative detection of metabolites
and characterization of their structures. Although the analytical
tools have progressed sufficiently to allow determination
of metabolites, proper in vitro models and in
vivo studies have to be carefully designed in order to
understand drug metabolism. Points for consideration when
conducting in vivo drug metabolism studies include
interspecies differences in systemic exposure and metabolism
pathways, identification of the major metabolites and unique
human metabolites that become the regulatory focus, local
metabolism in addition to liver metabolism, time points for
sampling, and synthesis of the authentic metabolites to confirm
their formation. The next part of this serial article will
focus on in vitro drug metabolism studies.
[Back to top]
The Conduct of Drug Metabolism Studies Considered
Good Practice (II): In Vitro Experiments
L. Jia and X. Liu
In vitro drug metabolism studies, which are inexpensive
and readily carried out, serve as an adequate screening mechanism
to characterize drug metabolites, elucidate their pathways,
and make suggestions for further in vivo testing.
This publication is a sequel to part I in a series and aims
at providing a general framework to guide designs and protocols
of the in vitro drug metabolism studies considered
good practice in an efficient manner such that it would help
researchers avoid common pitfalls and misleading results.
The in vitro models include hepatic and non-hepatic
microsomes, cDNA-expressed recombinant human CYPs expressed
in insect cells or human B lymphoblastoid, chemical P450 inhibitors,
S9 fraction, hepatocytes and liver slices. Important conditions
for conducting the in vitro drug metabolism studies
using these models are stated, including relevant concentrations
of enzymes, co-factors, inhibitors and test drugs; time of
incubation and sampling in order to establish kinetics of
reactions; appropriate control settings, buffer selection
and method validation. Separate in vitro data should
be logically integrated to explain results from animal and
human studies and to provide insights into the nature and
consequences of in vivo drug metabolism. This article
offers technical information and data and addresses scientific
rationales and practical skills related to in vitro
evaluation of drug metabolism to meet regulatory requirements
for drug development.
[Back to top]
Interactions of Polyphenolic Compounds with Drug Disposition
and Metabolism
F. Galli
Polyphenols are a heterogeneous class of compounds that include
several hydrosoluble antioxidants useful in food preservation
and claimed as health promoting agents. However, a number
of studies in recent years have demonstrated that this class
of compounds also contains powerful xenobiotics and cell stress
inducers, which in turn elicit responses of defence and adaptation
of the gastrointestinal tract and possibly of other organs.
These responses investigated both in vitro and in
vivo include the modulation of various groups of metabolic
and stress genes, as well as effects on the expression and
activity of detoxification systems, such as drug metabolising
enzymes (DMEs), antioxidant and phase II enzymes, and transporter
proteins. Such effects have been extensively interpreted as
useful in that they can produce greater protection against
xenobiotics and "cellular stresses" of endogenous
and exogenous origin, and may indicate a mechanism for the
preventive role that polyphenols are believed to play against
the degenerative events of aging and chronic diseases. Conversely,
these gene induction effects and the interaction with detoxification
responses can have negative consequences by the generation
of more reactive and harmful intermediates, and modified bioavailability
and in vivo bioactivity of drugs, nutrients and the
same polyphenols. This paper provides an overview of the recent
literature on the mechanisms that govern biochemical and molecular
responses to polyphenolic compounds relevant to drug metabolism,
disposition and therapeutic efficacy.
[Back to top]
Isoniazid: Metabolic Aspects and Toxicological Correlates
P. Preziosi
For over half a century, pyridine-4-carboxy hydrazide (isonicotinyl
hydrazide; isoniazid - INH) has been a front-line weapon in
the battle against tuberculosis. Its metabolism has been the
subject of important research, much of which has focused on
the pharmacodynamic and toxicological aspects of certain INH
metabolites. Since 1952, when the drug was first introduced,
multiple INH metabolites have been identified, including hydrazine
(HZ), isonicotinic acid (INA), ammonia, the acetylated
derivative N1-acetyl-N2-isonicotinylhydrazide
(AcINH), hydrazones with pyruvic and ketoglutaric acids (INH-PA
and INH-KA, respectively), monoacetylhydrazine (AcHZ), diacetylhydrazine
(DiAcHZ), and oxidizing free radicals. Their formation is
the result of hydrolysis (INA, HZ), cytochrome P450 (CYP)-dependent
oxidation (HZ, NH3, oxidizing
free radicals), and N-acetyltransferase (NAT) activity (AcINH,
AcHZ, DiAcHZ). Doubts remain about isonicotinamide (INAAM)
as an INH metabolite in mammals. Quantitatively speaking,
one of the major metabolites is AcINH, which is produced by
the enzyme NAT. It has virtually no antitubercular activity
and is far less toxic than INH. Its formation and elimination
are genetically controlled, and its elimination profile is
trimodal (rapid, intermediate, and slow acetylation). Slow
acetylation, which is transmitted as an autosomal recessive
trait, increases the risk for peripheral neurotoxicity and
hepatotoxicity in INH users. Thus far, there is no conclusive
pharmacogenetic evidence that the formation of HZ and oxidizing
radicals are linked to CYP polymorphisms.
This article examines INH, HZ and its mono- and diacetylated
metabolites, and ammonia (which in vitro and in
vivo studies indicate as another derivative of HZ) in
terms of their potential to cause neurotoxic and hepatotoxic
effects (the two major forms of INH toxicity observed in animals
and humans). INH hepatotoxicity seems to be related mainly
to HZ, AcHZ, and other HZ metabolites that are capable of
generating free radicals. The pathological aspects of slow
INH acetylation will be discussed in relation to the drug’s
hepato- and neurotoxic effects. The mechanism underlying INH
neurotoxicity has yet to be fully defined. The metabolite(s)
involved in this phenomenon remain obscure although a major
role is clearly played by HZ (and possibly also by the ammonia
it releases). There is some evidence of the involvement of
γ-glutamyl
HZ and of a chemical analogue of a Schiff base formed by INH
and pyridoxal-phosphate.
Recent findings have also revealed important interactions
between INH and the various isoforms of CYP, and these may
play a role in clinically relevant interactions between INH
and several other drugs. All of these aspects of INH will
be covered in the review.
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