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Current Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 7, Number 1, January 2006
Contents
Inhibition Constants, Inhibitor Concentrations and the Prediction
of Inhibitory Drug Drug Interactions: Pitfalls, Progress and
Promise Pp. 1-14
K.A. Bachmann
[Abstract]
Early Development of Therapeutic Biologics – Pharmacokinetics
Pp. 15-21
A. Baumann
[Abstract]
Cytochrome P450 and Anticancer Drugs Pp. 23-37
K.-i. Fujita
[Abstract]
Tissue Distribution and Pharmacodynamics: A Complicated Relationship
Pp. 39-65
J.H. Lin
[Abstract]
Altered CYP Expression and Function in Response to Dietary
Factors: Potential Roles in Disease Pathogenesis Pp. 67-81
M. Murray
[Abstract]
Inhibition of Sulfotransferases by Xenobiotics
Pp. 83-104
L.-Q. Wang and M.O. James
[Abstract]
Topotecan Is a Substrate for Multidrug Resistance
Associated Protein 4 Pp. 105-118
Q. Tian, J. Zhang, S.Y. Chan, T.M.C. Tan, W. Duan, M. Huang,
Y.-Z. Zhu, E. Chan, Q. Yu, Y.-Q. Nie, P.C.-L. Ho, Q. Li, K.-Y.
Ng, H.-Y. Yang, H. Wei, J.-S. Bian and S.-F. Zhou
[Abstract]
Abstracts
[Back to top]
Inhibition Constants, Inhibitor Concentrations and the
Prediction of Inhibitory Drug Drug Interactions: Pitfalls,
Progress and Promise
K.A. Bachmann
Strategies and standards for predicting the likelihood of
pharmacokinetically significant inhibitory drug-drug interactions
for drug development purposes which rely primarily on projected
in vivo concentrations of cytochrome P450 (CYP) or
transporter inhibitors, [I], and in vitro estimates
of their inhibitory constants, Ki, were specified
in several commentaries based upon a conference held by the
European Federation of Pharmaceutical Sciences (EUFEPS) several
years ago. Since then the application of those strategies
and standards has met with varying degrees of success. Many
of the vexing issues that were identified in the EUFEPS Conference
Report remain, while other issues are systematically being
resolved. This article briefly reviews the underlying strategy
in the prediction of the significance of inhibitory DDIs using
[I]/Ki ratios; some of the difficulties or pitfalls
associated with the predictive application of [I]/Ki
ratios; and some of the recent refinements of the general
strategy.
[Back to top]
Early Development of Therapeutic Biologics – Pharmacokinetics
A. Baumann
Modern biologics are biotechnology-derived pharmaceuticals.
They are mostly used for diagnosis, prevention and treatment
of serious and chronic diseases. Today, therapeutic biologics
range from traditional biologics like blood and blood components,
fractionated blood products, and antitoxins to modern biologics
such as monoclonal antibodies, cytokines (e.g. interferon,
interleukine), tissue growth factors, vaccines directed against
non-infectious disease targets, and gene transfer products.
Chemical as well as pre-clinical development are major challenges
for biologics due to their different physicochemical properties
(mostly protein structure) compared to small molecules. They
demonstrate much more complex pharmacoki-netic behaviour,
which strongly influences their pre-clinical testing strategy.
Biologics are often highly species-specific in action and
immunogenic in test animal species and humans. Immunogenicity
of therapeutic biologics may influence their pharmacokinetic
behaviour as well as pharmacodynamics and toxicity. Biologics
are frequently regulated by differ-ent procedures compared
to small molecules. New guidances are evolving which reflect
the rapid development of new technologies in this field. Bioanalytical
method development and validation is a prerequisite not exclusively
for pharma-cokinetic studies but for the whole pre-clinical
and clinical development. Due to their unique properties,
different kinds of bioanalytical assays (mass assays, activity
assays, immunogenicity assays) are necessary in early development
of bio-logics.
[Back to top]
Cytochrome P450 and Anticancer Drugs
K.-i. Fujita
Cytochrome P450 (CYP) is involved in the metabolism of a
variety of anticancer drugs. CYP activities are known to be
modified by several factors including genetic polymorphisms,
changes in physiological conditions such as age, disease status
or intake of certain drugs or foods or environmental factors
such as smoking. These factors may cause interindividual differences
in the pharmacokinetic profiles of anticancer drugs, leading
to the variations of efficacy or toxicity of the drugs.
Genetic polymorphisms present in CYPs sometimes result in
the reduced activity of the enzymes causing low metabolic
clearance of drugs or low production of active metabolites.
For example, the formation of endoxifen, which is an active
metabolite of tamoxifen, was less in patients with inactive
polymorphic CYP2D6 than those with the wild type enzyme.
CYP3A is the most abundant CYP expressed in the human liver
and the small intestine that is involved in the metabo-lism
of various anticancer drugs. The catalytic activity of CYP3A
shows a large interindividual variability giving rise to large
interindividual differences in the pharmacokinetic profiles
of some anticancer drugs. So far, many attempts have been
made to monitor the phenotypic activity of CYP3A in order
to reduce the pharmacokinetic variations of anticancer drugs.
Erythromycin, midazolam and cortisol are commonly used to
monitor in vivo hepatic CYP3A activity. These methods
have been applied to reduce the pharmacokinetic variations
of docetaxel.
Drug-drug interactions related to CYPs also modulate the
pharmacokinetic profiles of anticancer drugs.
These factors should be considered when trying to optimize
and individualize chemotherapy.
[Back to top]
Tissue Distribution and Pharmacodynamics: A Complicated
Relationship
J.H. Lin
With few exceptions, drugs exert their effects not within
the plasma compartment, but in the defined target tissues.
The process of drug distribution to the active site constitutes
the “link-bridge” of the pharmacokinetic/pharmacody-namic
(PK/PD) relationship. In spite of the importance of drug distribution
as a key factor in determining pharmacologic response, research
on drug distribution has historically received much less attention
than that of absorption, metabolism, and excretion. The negligence
of research on drug distribution is due mainly to the inaccessibility
of the target tissues for obvious ethical reasons. In addition,
lack of reliable experimental tools to assess the distribution
process is also a major contributing factor. Because of this
negligence, drug distribution has been referred to as “the
forgotten relative in clinical pharmacokinetics.” Although
recent advances in molecular biology have led to the identification
of many drug transporters, many of the processes of drug distribution
are still not fully understood. The primary aim of this article
is to provide new insight into the mechanisms of drug distribution,
with an attempt to describe the relationship between the drug
distribution and pharmacologic response. In addition, the
factors that affect the processes of drug distribution will
also be reviewed. Also, validity of some key assumptions that
are used to relate the processes of tissue distribution with
pharmacologic activity will be discussed.
[Back to top]
Altered CYP Expression and Function in Response to Dietary
Factors: Potential Roles in Disease Pathogenesis
M. Murray
Increasing evidence implicates dietary factors in the progression
of diseases, including certain cancers, diabetes and obesity.
Diet also regulates the expression and function of CYP genes,
which impacts on drug elimination and may also significantly
affect disease pathogenesis. Upregulation of CYPs 2E1 and
4A occurs after feeding of experimental diets that are high
in fats or carbohydrates; these diets also promote hepatic
lipid infiltration, which is a component of the metabolic
syndrome that characterises obesity. Increased availability
of lipid substrates for CYPs can enhance free radical production
and exacerbate tissue injury. Similar processes may also occur
in other models of experimental disease states that exhibit
a component of altered nutrient utilization.
Food-derived chemicals, including constituents of cruciferous
vegetables and fruits, modulate CYP expression and the expression
of genes that encode cytoprotective phase II enzymes. Certain
dietary indoles and flavonoids activate CYP1A expression either
by direct ligand interaction with the aryl hydrocarbon receptor
(AhR) or by augmenting the interaction of the AhR with xenobiotic
response elements in CYP1A1 and other target genes. Other
dietary chemicals, including methylenedioxyphenyl (MDP) compounds
and isothiocyanates also modulate CYP gene expression.
Apart from altered CYP regulation, a number of dietary agents
also inhibit CYP enzyme activity, leading to pharma-cokinetic
interactions with coadministered drugs. A well described example
is that of grapefruit juice, which contains psoralens and
possibly other chemicals, that inactivate intestinal CYP3A4.
Decreased presystemic oxidation by this CYP increases the
systemic bioavailability of drug substrates and the likelihood
of drug toxicity. Dietary interactions may complicate drug
therapy but inhibition of certain CYP reactions may also protect
the individual against toxic me-tabolites and free radicals
generated by CYPs. Chemicals in teas and cruciferous vegetables
may also inhibit human CYP enzymes that have been implicated
in the bioactivation of chemical carcinogens. Thus, food constituents
modulate CYP expression and function by a range of mechanisms,
with the potential for both deleterious and beneficial outcomes.
[Back to top]
Inhibition of Sulfotransferases by Xenobiotics
L.-Q. Wang and M.O. James
The sulfotransferase (SULT) family comprises important phase
II conjugation enzymes for the detoxification of xenobiotics
and modulation of the activity of physiologically important
endobiotics such as thyroid hormones, steroids, and neurotransmitters.
SULT enzymes catalyze the transfer of a sulfuryl group, donated
by 3'-phosphoadenosine-5'-phosphosulfate (PAPS), to an acceptor
substrate that may be a hydroxy group or an amine group in
a process originally called sulfation, but more correctly
referred to as sulfonation or sulfurylation. SULT activity
may be inhibited when humans are exposed to certain xenobiotics
including drugs (mefenamic acid, salicylic acid, clomiphene,
danazol etc.), dietary chemicals (catechins, food colorants,
flavonoids and phytoestrogens etc.), and environmental chemicals
(hydroxylated polychlorinated biphenyls, hydroxylated polyhalogenated
aromatic hydrocarbons, pentachlorophenol, triclosan and bisphenol
A, etc.). Inhibition of individual SULT isoforms may cause
adverse effects on human health. For example, hydroxylated
polychlorinated biphenyls have been shown to interfere with
the transport of thyroid hormones, inhibit estradiol sulfonation,
and inhibit thyroid hormone sulfonation, thereby potentially
disrupting the thyroid hormone system. Formation of sulfate
conjugates of toxic xenobiotics usually decreases their toxicity,
so inhibition of this path-way may lead to prolonged exposure
to the compounds. Conversely, some sulfate conjugates are
chemically reactive, in-hibition of their formation may protect
from toxicity. This manuscript will review the literature
concerning the inhibition of SULTs by xenobiotics including
isoform-selective effects, inhibition kinetics and health
effects resulting from the inhibition.
[Back to top]
Topotecan Is a Substrate for Multidrug Resistance
Associated Protein 4
Q. Tian, J. Zhang, S.Y. Chan, T.M.C. Tan, W. Duan, M. Huang,
Y.-Z. Zhu, E. Chan, Q. Yu, Y.-Q. Nie, P.C.-L. Ho, Q. Li, K.-Y.
Ng, H.-Y. Yang, H. Wei, J.-S. Bian and S.-F. Zhou
Topotecan (TPT) is a semisynthetic water-soluble derivative
of camptothecin (CPT) used as second-line therapy in patients
with metastatic ovarian carcinoma, small cell lung cancer,
and other malignancies. However, both dose-limiting toxicity
and tumor resistance hinder the clinical use of TPT. The mechanisms
for resistance to TPT are not fully defined, but increased
efflux of the drug by multiple drug transporters including
P-glycoprotein (PgP), multidrug resistance associated protein
1 (MRP1) and breast cancer resistance protein (BCRP) from
tumor cells has been highly implicated. This study aimed to
investigate whether overexpression of human MRP4 rendered
resistance to TPT by examining the cytotoxicity profiles using
the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide
(MTT) assay and cellular accumulation of TPT in HepG2 cells
stably overexpressing MRP4. Two kinds of cell lines, HepG2
with insertion of an empty vector plasmid (V/HepG2), HepG2
cells stably expressing MRP4 (MRP4/HepG2), were exposed to
TPT for 4 or 48 hr in the absence or presence of various MRP4
inhibitors including DL-buthionine-(S,R)-sulphoximine (BSO),
diclofenac, celecoxib, or MK-571. The intracellular accumulation
of TPT and paclitaxel (a PgP substrate) by V/HepG2 and MRP4/HepG2
cells was determined by incubation of TPT with the cells and
the amounts of the drug in cells were determined by validated
HPLC methods. The study demonstrated that MRP4 conferred a
12.03- and 6.86-fold resistance to TPT in the 4- and 48-hr
drug-exposure MTT assay, respectively. BSO, MK-571, celecoxib,
or diclofenac sensitised MRP4/HepG2 cells to TPT cytotoxicity
and partially reversed MRP4-mediated resistance to TPT. In
addition, the accumulation of TPT was significantly reduced
in MRP4/HepG2 cells compared to V/HepG2 cells, and one-binding
site model was found the best fit for the MRP4-mediated efflux
of TPT, with an estimated Km of 1.66 μM
and Vmax of 0.341 ng/min/106 cells.
Preincubation of MRP4/HepG2 cells with BSO (200 μM)
for 24 hr, celecoxib (50 μM),
or MK-571 (100 μM)
for 2 hr significantly increased the accumulation of TPT over
10 min in MRP4/HepG2 cells by 28.0%, 37.3% and 32.5% (P
< 0.05), respectively. By contrast, there was no significant
difference in intracellular accumulation of paclitaxel in
V/HepG2 and MRP4/HepG2 cells over 120 min. MRP4 also rendered
resistance to adefovir dipivoxil (bis-POM-PMEA) and methotrexate,
two reported MRP4 substrates. MRP4 did not exhibit any significant
resistance to other model drugs including vinblastine, vincristine,
etoposide, carboplatin, cyclosporine and paclitaxel in both
long (48 hr) and short (4 hr) drug-exposure MTT assays. These
findings indicate that MRP4 confers resistance to TPT and
TPT is the substrate for MRP4. Further studies are needed
to explore the role of MRP4 in resistance to, toxicity and
pharma-cokinetics of TPT in cancer patients.
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