Drug
Metabolism Letters
ISSN: 1872-3128
Drug Metabolism Letters
Volume 1, Number 2, April 2007
Contents
Peroxynitrite Induces Apoptosis and Decline in
Intracellular Free Mg with Concomitant Elevation in [Ca2+]i
in Rat Aortic Smooth Muscle Cells: Possible Roles of Extracellular
and Intracellular Magnesium Ions in Peroxynitrite-Induced
Cell Death Pp. 85-89
J. Li, W. Li, W. Liu, B.T. Altura and B.M. Altura
[Abstract]
An Estimate of the Number of Hepatocyte Donors Required
to Provide Reasonable Estimates of Human Hepatic Clearance
from In Vitro Experiments Pp. 91-95
J. Byers, K. Bachmann, H. Eng, A. Katta, D. White, R.
Ghosh, N.J. Hewitt, P. Silber and G. Chen
[Abstract]
Involvement of Cytochromes P450 2D6, 2B6 and 2C19
in the Metabolism of (-)-Deprenyl and N-Methyl,N propargylphenylethylamine
Pp. 97-100
K.A. Rittenbach and G.B. Baker
[Abstract]
A Glucuronidation Pathway of Capecitabine Occurs in
Rats but Not in Mice and Humans Pp. 101-107
F. Desmoulin, C. Claparols, D. Bon, G. Larrieu, R. Martino
and M. Malet-Martino
[Abstract]
Assessment of Cryopreserved Hepatocytes as an Alternative
to Fresh Hepatocytes for Comparative Interspecies Metabolism
Studies with Suitable Acceptance Criteria Pp. 109-120
Z. (Zack) Cheng, C.E. Herron, G. Bowers and M. de Serres
[Abstract]
The Human Sperm Glutathione System: A Key Role in
Male Fertility and Successful Cryopreservation Pp.
121-126
M. Meseguer, J.A. Martínez-Conejero, L. Muriel,
A. Pellicer, J. Remohí and N. Garrido
[Abstract]
Application of Simple Mathematical Expressions to
Relate Half-Lives of Drugs in Mice to Those in Humans
Pp. 127-129
K. Bachmann, J. Chupka, P. Erhardt and D. White
[Abstract]
Intracellular Delivery of Nanogel-Quantum Dot Hybrid
Nanoparticles into Human Periodontal Ligament Cells
Pp. 131-135
T. Fukui, H. Kobayashi, U. Hasegawa, T. Nagasawa, K. Akiyoshi
and I. Ishikawa
[Abstract]
Brief Review of Polymorphic Drug-Metabolizing Enzymes
in Japanese Populations: Development of a Higher-Throughput
Genotyping Method and Proposed Applications Pp. 137-142
T. Kubota
[Abstract]
Resin-Salve from Norway Spruce - A Potential Method
to Treat Infected Chronic Skin Ulcers? Pp. 143-145
A. Sipponen, M. Rautio, J.J. Jokinen, T. Laakso, P. Saranpää
and J. Lohi
[Abstract]
The Utility of Stable Cell Lines to Assess Species
Differences in PXR Transactivation Pp. 147-152
M.W. Sinz, D. Pray and J. Raucy
[Abstract]
Disposition of Vorinostat, A Novel Histone Deacetylase
Inhibitor and Anticancer Agent, in Preclinical Species
Pp. 153-161
P. Sandhu, P.A. Andrews, M.P. Baker, K.A. Koeplinger,
E.D. Soli, T. Miller and T.A. Baillie
[Abstract]
Frequency of CYP1A2 Polymorphism in Beagle Dogs
Pp. 163-165
V.J. Whiterock, T.A. Delmonte, L.E. Hui, T.L. Orcutt and
M.W. Sinz
[Abstract]
Abstracts
[Back to top]
Peroxynitrite Induces Apoptosis and Decline in
Intracellular Free Mg with Concomitant Elevation in [Ca2+]i
in Rat Aortic Smooth Muscle Cells: Possible Roles of Extracellular
and Intracellular Magnesium Ions in Peroxynitrite-Induced
Cell Death
J. Li, W. Li, W. Liu, B.T. Altura and B.M. Altura
The present study demonstrates that exogenous ONOO-
can result in rapid declines in intracellular free magnesium
ions ([Mg2+]i) concomitant with rapid
rises in intracellular free calcium ions ([Ca2+]i)
and, subsequently, trigger apoptosis but not necrosis in rat
aortic SMCs; high [Mg2+] significantly attenuates
ONOO--induced apoptosis. ONOO--induced
apoptosis in vascular SMCs appears to involve activation of
Ca2+-Mg2+-dependent endonucleases and
caspase-3. Mg deficiency itself could not induce apoptosis
in these SMCs, but it could significantly enhance ONOO--induced
apoptosis.
[Back to top]
An Estimate of the Number of Hepatocyte Donors Required
to Provide Reasonable Estimates of Human Hepatic Clearance
from In Vitro Experiments
J. Byers, K. Bachmann, H. Eng, A. Katta, D. White, R.
Ghosh, N.J. Hewitt, P. Silber and G. Chen
Cryopreserved human hepatocytes in suspension were used to
estimate in vivo hepatic clearances for six different
drugs. In vitro intrinsic clearances were measured
on the basis of substrate depletion. The number of different
hepatocyte donors required for a reasonable estimate of in
vivo hepatic clearance—within twice or ½
of the actual value—was determined. Depending upon the
desired level of confidence, anywhere from 9-20 donors are
required by this method.
[Back to top]
Involvement of Cytochromes P450 2D6, 2B6 and 2C19
in the Metabolism of (-)-Deprenyl and N-Methyl,N propargylphenylethylamine
K.A. Rittenbach and G.B. Baker
The metabolism of (-)-deprenyl (N-methyl,N-propargylamphetamine)
and N-methyl,N-propargylphenyl-ethylamine (MPPE), monoamine
oxidase inhibitors with neuroprotective properties, was studied
using human liver microsomes and cDNA-expressed cytochrome
P450 (CYP) enzymes. The metabolic pathways of MPPE parallel
those of (-)-deprenyl, but some marked differences were observed,
particularly with regard to the contributions of CYP2B6 and
CYP2D6.
[Back to top]
A Glucuronidation Pathway of Capecitabine Occurs in
Rats but Not in Mice and Humans
F. Desmoulin, C. Claparols, D. Bon, G. Larrieu, R. Martino
and M. Malet-Martino
Glucuronidation of 5’-DFCR, a metabolite of capecitabine,
was confirmed in experimental models from rats whereas 5’-DFCR
glucuronide was detected neither in bile or liver from mice
nor in liver microsomes from human. Metabolic interactions
at the level of the glucuronidation pathway between CAP and
other drugs are unlikely in patients.
[Back to top]
Assessment of Cryopreserved Hepatocytes as an Alternative
to Fresh Hepatocytes for Comparative Interspecies Metabolism
Studies with Suitable Acceptance Criteria
Z. (Zack) Cheng, C.E. Herron, G. Bowers and M. de Serres
Fresh hepatocytes have been the choice for interspecies comparative
drug metabolism studies. Cryopreserved hepatocytes represent
a readily available alternative when combined with acceptance
limits based on the metabolic turnover of 7-ethoxycoumarin.
Results for the ten NCEs examined show that the metabolites
formed were strongly correlated in fresh and cryopreserved
hepatocytes.
[Back to top]
The Human Sperm Glutathione System: A Key Role in
Male Fertility and Successful Cryopreservation
M. Meseguer, J.A. Martínez-Conejero, L. Muriel,
A. Pellicer, J. Remohí and N. Garrido
The equilibrium of the creation and scavenging of free radicals
is mandatory in the spermatozoa to fertilize and initiate
a full-term pregnancy. The glutathione (GSH) enzymatic system
studies have discovered its relationship with oxidative stress
in the ejaculate and new strategies to regulate its activity
in the semen could be developed.
Intracellular sperm GSH system components are altered in infertile
men, and these alterations seem to be linked to sperm morphology.
We have been able to correlate embryo morphology on 8 cell
embryos with the sperm expression of GPx family members; this
relationship appears quite promising for discovery of molecular
causes of male infertility.
Oxidative stress imbalance potentially leads to damage of
the structure of plasma membrane. The freezing and subsequent
thawing of sperm is a physically stressful process carried
out during routine procedures in assisted reproduction, which
results in a highly variable and unpredictable reduction of
motile sperm. Subsequently, oxidative status can positively
or negatively affect the motility, viability, and fertilizing
capacity of thawed sperm. A reserve of glutathione, together
with GPx expression, is necessary to eliminate free radicals
using GSH or GPx-4 like structural protein and seems to be
essential for a good post thaw recovery.
[Back to top]
Application of Simple Mathematical Expressions to
Relate Half-Lives of Drugs in Mice to Those in Humans
K. Bachmann, J. Chupka, P. Erhardt and D. White
The use of rat half-life data to predict human half-lives
for drugs and other xenobiotics has previously been shown
to be of value. Since transgenic and knockout mice are increasingly
used in early stages of preclinical drug development, we wondered
whether the estimation of half-life values in mice might be
used in the same way that has been recommended for rats. A
dataset of mouse and human half-life values was assembled
for 88 drugs. Three different regression models were then
applied to the prediction of human half-life values from mouse
values. The results showed that none of the models was superior
to any other, and that all models, including the simplest
linear regression model, could predict a human half-life value
from a mouse half-life value such that there would be an 80%
chance that the predicted value would be within three-fold
(i.e. between 0.33 times and 3 times) of the actual human
value.
[Back to top]
Intracellular Delivery of Nanogel-Quantum Dot Hybrid
Nanoparticles into Human Periodontal Ligament Cells
T. Fukui, H. Kobayashi, U. Hasegawa, T. Nagasawa, K. Akiyoshi
and I. Ishikawa
Nanogels of cholesterol-bearing pullulan modified with amino-groups
(CHPNH2) were utilized as a career to introduce
quantum dots (QDs) into periodontal ligament (PDL) cells.
Nanogel-QD effectively labeled PDL cells over 3 weeks. These
results indicate that CHPNH2nanogels have a potential as a
research tool in the studies of intracellular delivery system.
[Back to top]
Brief Review of Polymorphic Drug-Metabolizing Enzymes
in Japanese Populations: Development of a Higher-Throughput
Genotyping Method and Proposed Applications
T. Kubota
Different functional alleles for each subtype of cytochrome
P450 (CYPs), thiopurine S-methyltransferase (TPMT), glutathione
S-transferase (GST) and sulfotransferase (SULT) enzymes, have
been identified. In this review, the genetic polymorphisms
of drug-metabolizing enzymes in the Japanese population and
their effects on metabolic activity are described in detail.
[Back to top]
Resin-Salve from Norway Spruce - A Potential Method
to Treat Infected Chronic Skin Ulcers?
A. Sipponen, M. Rautio, J.J. Jokinen, T. Laakso, P. Saranpää
and J. Lohi
The home-made resin salve from Norway spruce is traditionally
and widely used in folk medicine to heal various skin infections
and wounds in Northern Finland. We have performed laboratory
studies to solve the mechanism of resin salve. The resin salve
exhibited a bacteriostatic effect against all tested Gram-positive
bacteria important in human medicine including methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resistant
enterococcus (VRE), but was not effective against Gram-negative
bacteria. An exception among the Gram-negative bacteria was
Proteus vulgaris against which resin salve was effective.
High amounts of lipophilic extractives, like resin acids were
dissolved into water from the resin salve. Also, a large proportion
of lignans and cinnamic acid were found in the water extract.
[Back to top]
The Utility of Stable Cell Lines to Assess Species
Differences in PXR Transactivation
M.W. Sinz, D. Pray and J. Raucy
A stable cell line was developed to assess activation of rat
pregnane X receptor (rPXR) by xenobiotics. Characterization
revealed that the greatest response occurred with dexamethasone
(6-10 fold increase) while rifampicin failed to transactivate
rPXR. Rodent PXR transactivation assays can be used to understand
species differences in enzyme induction.
[Back to top]
Disposition of Vorinostat, A Novel Histone Deacetylase
Inhibitor and Anticancer Agent, in Preclinical Species
P. Sandhu, P.A. Andrews, M.P. Baker, K.A. Koeplinger,
E.D. Soli, T. Miller and T.A. Baillie
The disposition of vorinostat, an anticancer agent, was investigated
in rats and dogs. Vorinostat possessed high serum clearance,
a short elimination half-life and low oral bioavailability
in both species. The renal route played an important role
in the elimination of drug-related material and vorinostat
was eliminated primarily by metabolic biotransformation.
[Back to top]
Frequency of CYP1A2 Polymorphism in Beagle Dogs
V.J. Whiterock, T.A. Delmonte, L.E. Hui, T.L. Orcutt and
M.W. Sinz
A single nucleotide polymorphism in the dog CYP1A2
gene causes these animals to be CYP1A2 deficient (i.e., lack
functional CYP1A2 enzyme activity). Genotyping a colony of
79 dogs revealed 77% wild-type, 19% heterozygous, and 4% homozygous
mutant animals. These genetic frequencies are significantly
different from those previously reported and illustrate that
different sources and populations of dogs can have dramatically
different frequencies of this polymorphism.
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