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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 11, Number 6, July 2010
Contents
Applications of LC-MS in PET Radioligand Development and Metabolic
Elucidation Pp. 483-493
Y. Ma, D.O. Kiesewetter, L. Lang, D. Gu and
X. Chen
[Abstract] [Purchase
Article]
Dihydrocodeine as an Opioid Analgesic for the Treatment of
Moderate to Severe Chronic Pain Pp. 494-506
W. Leppert
[Abstract]
[Purchase Article]
Specific Hemosiderin Deposition in Spleen Induced by a Low
Dose of Cisplatin: Altered Iron Metabolism and Its Implication
as an Acute Hemosiderin Formation Model Pp. 507-515
Y. Wang, J. LV, X. Ma, D. Wang, H. Ma, Y. Chang,
G. Nie, L. Jia, X. Duan and X.-J. Liang
[Abstract] [Purchase
Article]
Atypical Antipsychotic Metabolism and Excretion Pp.
516-525
J.J. Sheehan, J.K. Sliwa, J.C. Amatniek, A. Grinspan
and C.M. Canuso
[Abstract] [Full
Text Article]
Systematic Evaluation of Dose Proportionality
Studies in Clinical Pharmacokinetics Pp. 526-537
Y. Sheng, Y. He, X. Huang, J. Yang, K. Wang and
Q. Zheng
[Abstract] [Full
Text Article]
Zebrafish as a Model for the Study of the Phase II
Cytosolic Sulfotransferases Pp. 538-546
T.-A. Liu, S. Bhuiyan, M.-Y. Liu, T. Sugahara, Y. Sakakibara,
M. Suiko, S. Yasuda, Y. Kakuta, M. Kimura, F.E. Williams and
M.-C. Liu
[Abstract]
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Article]
Enzyme Stereospecificity as a Powerful Tool in Searching
for New Enzymes Pp. 547-559
L. Škarydová, A. Skarka, P. Solich and
V. Wsól
[Abstract]
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Article]
Addendum
Abstracts
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Applications of LC-MS in PET Radioligand
Development and Metabolic Elucidation
Y. Ma, D.O. Kiesewetter, L. Lang, D. Gu and
X. Chen
Positron emission tomography (PET) is a very
sensitive molecular imaging technique that when employed with
an appropriate radioligand has the ability to quantititate
physiological processes in a non-invasive manner. Since the
imaging technique detects all radio-active emissions in the
field of view, the presence and biological activity of radiolabeled
metabolites must be determined for each radio-ligand in order
to validate the utility of the radiotracer for measuring the
desired physiological process. Thus, the identification of
meta-bolic profiles of radiolabeled compounds is an important
aspect of design, development, and validation of new radiopharmaceuticals
and their applications in drug development and molecular imaging.
Metabolite identification for different chemical classes of
radiopharma-ceuticals allows rational design to minimize the
formation and accumulation of metabolites in the target tissue,
either through enhanced excretion or minimized metabolism.
This review will discuss methods for identifying and quantitating
metabolites during the pre-clinical development of radiopharmaceuticals
with special emphasis on the application of LC/MS.
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Dihydrocodeine as an Opioid Analgesic for the
Treatment of Moderate to Severe Chronic Pain
W. Leppert
Dihydrocodeine (DHC) is a semi-synthetic analogue of
codeine which was formed by the hydrogenation of the double
tie in the main chain of the codeine molecule. DHC is used
as an analgesic, antitussive and antidiarrhoeal agent; it
is also used for the treatment of opioid addiction. Limited
data is available on the relative potency of DHC to other
opioids. The analgesic effect of DHC is probably twice as
potent as codeine for the parenteral and slightly stronger
for an oral route. DHC possesses approximately 1/6th
of the morphine analgesic effect when drugs are administered
orally. In this article pharmacokinetics, pharmacodynamics,
dosing guidelines, adverse ef-fects and clinical studies of
DHC in pain management are shown with focus on cancer pain.
The impact of CYP2D6 activity on DHC an-algesia was discussed
and a proposal of calculation equianalgesic doses of DHC to
other opioids was put forward.
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Specific Hemosiderin Deposition in Spleen Induced
by a Low Dose of Cisplatin: Altered Iron Metabolism and Its
Implication as an Acute Hemosiderin Formation Model
Y. Wang, J. LV, X. Ma, D. Wang, H. Ma, Y. Chang,
G. Nie, L. Jia, X. Duan and X.-J. Liang
Cisplatin is one of the commonly-used chemotherapeutic
drugs to efficiently treat malignant tumors in clinic, however,
the adverse effects of cisplatin such as nephrotoxicity, neurotoxcity,
and hemolytic uremic syndrome are often observed at its clinical
doses (~60 mg/m2), which
limit its broader application. In earlier studies, little
attention was paid to the subtle changes in the architecture
of lymphatic organs after low doses of cisplatin treatment.
This paper reviews current understanding of cisplatin-induced
erythrocyte injury, and presents our latest finding that a
low dose of cisplatin (3.6 mg/m2/day,
14 days) could induce specific hemosiderin deposition in spleen
of both normal and hepatoma-22 (H22) inoculated Balb/C mice.
This dose of cisplatin significantly inhibited H22-induced
acute ascites development. No significant toxicity was induced
by this dose of cisplatin to tissues except for hemosiderin
accumulation in the spleen of both normal and H22 tumor-bearing
mice. Increased splenic iron content and erythrocyte injury
were observed after treatment with the low dose of cisplatin.
The mRNA levels of ferroportin (FPN1) and ferritin were upregulated
by 25 and 5-fold in spleen, respec-tively. Overexpression
of FPN1 and ferritin protein were also been observed at protein
levels by Western blotting analysis. In addition, the mRNA
expression of hepcidin was also increased, suggesting blockage
of iron recycling through FPN1 in spleen with cisplatin treat-ment.
In conclusion, cisplatin treatment damages the erythrocytes
which accumulate in the red pulp of spleen with defective
recycling of FPN1 and ferritin protein. Hepcidin inhibits
the function of FPN1 as iron-exporter leading to iron overloaded
inside ferritins of splenic cells, which are stained with
abnormal hemosiderin accumulation. These results demonstrate
that cisplatin-caused hemosiderin deposition in spleen provides
a valuable clue for understanding the molecular basis of toxicity
of cisplatin and hemosiderin accumulation and iron metabolism
in vivo.
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[Full
Text Article]
Atypical Antipsychotic Metabolism and Excretion
J.J. Sheehan, J.K. Sliwa, J.C. Amatniek, A. Grinspan
and C.M. Canuso
Background: The metabolic/biotransformation pathways
of atypical antipsychotics (aripiprazole, clozapine, iloperidone,
olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone)
have been characterized and reviewed. However, comparisons
of excretory pathways remain unexplored. Objective:
To analyze the excretion profile of atypical antipsychotic
agents and compare the overall magni-tude of metabolism (changed
vs. unchanged drug) and route of excretion (feces vs. urine).
Secondary objectives include providing: 1) dosing information
in hepatic and renal impairment, and 2) context of the specific
enzymes and pathways involved in each agent’s bio-transformation.
Methods: Published literature and each manufacturer’s
radiolabeled drug absorption, distribution, metabolism and
excre-tion data and U.S. prescribing information were reviewed.
Results: With the exception of paliperidone, atypical
antipsychotics undergo extensive metabolism (i.e., ≤50%
of dose recovered unchanged). Quetiapine undergoes the greatest
overall metabolism (<1% of the dose recovered unchanged)
and paliperidone the least (59% recovered unchanged in the
urine). Between-agent differences exist in the extent of cytochrome
P450 (CYP450) metabolism and the specific isozymes involved.
After administration of a radioactive dose, fecal elimina-tion
of unchanged drug plus metabolites ranged from 11% (paliperidone)
to 71% (ziprasidone) and renal elimination ranged from 21%
(ziprasidone) to 80% (paliperidone). Conclusions:
Understanding the differences in the elimination profiles
of atypical antipsychotics agents may permit better-informed
drug and dose selection in special populations such as those
with comorbid conditions (e.g. hepatitis, diabetes, end-stage
renal disease) or pharmacogenetic variability; or at risk
for drug-drug interactions. The use of patient tailored drug
and dose-selection may result in greater treatment efficacy
and a reduction in adverse events.
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[Full Text Article]
Systematic Evaluation of Dose Proportionality
Studies in Clinical Pharmacokinetics
Y. Sheng, Y. He, X. Huang, J. Yang, K. Wang and
Q. Zheng
An understanding of dose proportionality is essential
in drug development, and the results are of great clinical
importance for predicting the effects of dose adjustments.
However, little consensus exists with regard to study design
and analysis. The aim of this paper was to produce a detailed
profile of the information on dose proportionality studies
in the last 10 years and to provide a foundation for reflection
and debate on future priorities. A total of 147 publications
comprising 156 studies were analyzed. The typical dose proportionality
study enrolled 20 to 30 subjects and randomly allocated them
into 3 to 4 dose levels to investigate pharmacokinetic behaviors
within a dose ratio range of 2-6. The most common design was
the crossover experiment (52.6%), and evaluating dose-adjusted
pharmacokinetic parameters followed by hypothesis testing
(43%) was the most frequent statistical approach. However,
the alternative crossover design and equivalence criterion
based on the power model represented only 4% and 8% of studies,
respectively. The power model as a recommendable empirical
relationship to assess dose proportionality was applied in
25 (16%) studies. This research suggests that the al-ternative
crossover design and power model statistical method should
be attracting more attention in order to obtain more information
in studies with limited subjects.
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Zebrafish as a Model for the Study of the Phase
II Cytosolic Sulfotransferases
T.-A. Liu, S. Bhuiyan, M.-Y. Liu, T. Sugahara, Y. Sakakibara,
M. Suiko, S. Yasuda, Y. Kakuta, M. Kimura, F.E. Williams and
M.-C. Liu
Cytosolic sulfotransferases (SULTs) are traditionally
known as the Phase II drug-metabolizing or detoxifying enzymes
that serve for the detoxification of drugs and other xenobiotics.
These enzymes in general catalyze the transfer of a sulfonate
group from the active sulfate, 3’-phophoadenosine 5’-phosphosulfate
(PAPS), to low-molecular weight substrate compounds containing
hydroxyl or amino group(s). Despite considerable efforts made
in recent years, some fundamental aspects of the SULTs, particularly
their ontogeny, cell type/tissue/organ-specific distribution,
and physiological relevance, particularly their involvement
in drug metabolism and detoxification, still remain poorly
understood. To better understand these fundamental issues,
we have embarked on developing the zebrafish as a model for
studies concerning the SULTs. To date, fifteen zebrafish SULTs
have been cloned, expressed, purified, and characterized.
These zebrafish SULTs, which fall into four major SULT gene
families, exhibited differential substrate specificities and
distinct patterns of expression at different stages during
embryogenesis, through larval development, and on to maturity.
The information obtained, as summarized in this review, provides
a foundation for further investigation into the physiological
and pharmacological involvement of the SULTs using the zebrafish
as a model.
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Enzyme Stereospecificity as a Powerful Tool in
Searching for New Enzymes
L. Škarydová, A. Skarka, P. Solich and
V. Wsól
Chirality is a ubiquitous feature present in all biological
systems that plays a very important role in many processes.
Drug metabolism is one of these and is the subject of this
review. Chiral drugs can be metabolized without changes in
their chiral characteristics, but also their biotransformation
may give rise to a new chiral center. On the other hand, prochiral
drugs are always metabolized to chiral metabolites. The ratio
of formed enantiomers/diastereoisomers is the constant known
as enzyme stereospecificity, and this is as important a characteristic
for each enzyme-substrate pair as is the Michaelis constant.
Drugs are often substrates for multiple biotransformation
en-zymes, and all enzymes involved may metabolize a chiral
or prochiral drug with different stereospecificity so that
variant enantiomer ra-tios are achieved. Enzyme stereospecificity
of whole cell fraction is the sum of the stereospecificities
of all enzymes participating in me-tabolism of a substrate.
Differing stereospecificities in the metabolism of a drug
between whole cell fraction and enzymes point to the contribution
of other enzymes. Using several drugs as examples, this review
shows that enzyme stereospecificity can serve as a powerful
tool in searching for new biotransformation enzymes. Although
it is not often used in this way, it is clear that this is
possible. There are today drugs with well-known chiral metabolism,
but, inasmuch as many xenobiotics are poorly characterized
in terms of chiral metabo-lism, enzyme stereospecificity could
be widely utilized in researching such substances.
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