Drug
Metabolism Letters
ISSN: 1872-3128
Drug Metabolism Letters
Volume 2, Number 2, April 2008
Contents
Influence of ABCB1 Gene Polymorphisms
and P-Glycoprotein Activity on Cyclosporine Pharmacokinetics
in Peripheral Blood Mononuclear Cells in Healthy Volunteers
Pp. 76-82
Nicolas Ansermot, Michela Rebsamen, Jocelyne Chabert, Marc
Fathi, Marianne Gex-Fabry, Youssef Daali, Marie Besson, Michel
Rossier, Serge Rudaz, Denis Hochstrasser, Pierre Dayer and
Jules Desmeules
[Abstract]
Synthesis and Evaluation of Macromolecule-Bound Derivatives
of a Peptidyl-1-β-D-arabinofuranosylcytosine
Prodrug Pp. 83-89
Zoltan Balajthy
[Abstract]
Brain-to-Plasma Distribution Ratio of the Biflavone
Amentoflavone in the Mouse Pp. 90-94
Milena Colovic, Claudia Fracasso and Silvio Caccia
[Abstract]
The Effects of the 3,4-Methylenedioxymethamphetamine
(Ecstasy) in Some Cerebral Areas: Role of the Oxidative Stress
Pp. 95-99
Sergio Franzese and Anna Capasso
[Abstract]
Analysis of Flavin-Containing Monooxygenase 3
Genotype Data in Populations Administered the Anti-Schizophrenia
Agent Olanzapine Pp. 100-114
John R. Cashman, Jun Zhang, Matthew R. Nelson and Andreas
Braun
[Abstract]
Effect of Folic Acid on Methotrexate Induction
of Sulfotransferases in Rats Pp. 115-119
Sangita Maiti Dutta, Smarajit Maiti and Guangping Chen
[Abstract]
The Use of 1-Aminobenzotriazole in Differentiating
the Role of CYP-Mediated First Pass Metabolism
and Absorption in Limiting Drug Oral Bioavailability: A Case
Study Pp. 120-124
Ayman F. El-Kattan, Julie Poe, Lisa Buchholz, Hayden V.
Thomas, Joanne Brodfuehrer and Alan Clark
[Abstract]
Stability of Methadone and Its Main Metabolite in
Oral Fluid Pp. 125-129
Nadia Fucci and Nadia De Giovanni
[Abstract]
Quantitative Structure-Retention-Pharmacokinetic Relationship
Studies Pp. 130-137
Snezana Agatonovic-Kustrin, Joseph V. Turner and Beverley
D. Glass
[Abstract]
Long Term Treatment with Tetradecylthioacetic Acid
Improves the Antioxidant Status in Obese Zucker (fa/fa) Rats
Pp. 138-145
Hege Wergedahl, Kjetil Berge, Pavol Bohov, Karl-Johan
Tronstad, Lise Madsen and Rolf K. Berge
[Abstract]
Pharmacokinetics and Metabolism of Diltiazem Following
Multiple Doses: Comparing Normotensive Rat vs Hypertensive
Rat Models In vivo Pp. 146-150
Pollen K.F. Yeung, Angelita Alcos, Jinglan Tang and William
L. Casley
[Abstract]
Abstracts
[Back to top]
Influence of ABCB1 Gene Polymorphisms
and P-Glycoprotein Activity on Cyclosporine Pharmacokinetics
in Peripheral Blood Mononuclear Cells in Healthy Volunteers
Nicolas Ansermot, Michela Rebsamen, Jocelyne Chabert, Marc
Fathi, Marianne Gex-Fabry, Youssef Daali, Marie Besson, Michel
Rossier, Serge Rudaz, Denis Hochstrasser, Pierre Dayer and
Jules Desmeules
The calcineurin inhibitor cyclosporine is removed from
lymphocytes by the drug efflux transporter P-glycoprotein
(P-gp) encoded by the ABCB1 gene for which several single
nucleotide polymorphisms (SNPs) have been identified. Of a
total of 87 healthy volunteers genotyped for ABCB1
G2677T/A and C3435T SNPs, 10 GG-CC and 9 TT-TT individuals
were selected and received a single oral dose of cyclosporine.
Peripheral blood mononuclear cell (PBMC) ABCB1 mRNA
expression, P-gp activity in CD4+
and CD8+ cells and the 24h
cyclosporine pharmacokinetics in PBMCs and whole blood were
determined. No correlation was observed between cyclosporine
PBMC and whole blood levels (AUC0-24, Spearman, rS=0.09, p=0.71).
Intraindividual PBMC and whole blood levels followed parallel
profiles that did not significantly differ with respect to
tmax Wilcoxon, p=0.53) and
t1/2 (p=0.49). Significant
negative correlations between cyclosporine t1/2
in PBMCs and P-gp activity in CD4+
(rS=-0.82, p=0.007) and CD8+
(rS= 0.72, p=0.03) were observed among TT TT subjects. Similarly,
a negative correlation was detected in the GG-CC group between
P gp activity in CD4+ and
cyclosporine PBMC AUC0-24
(rS=-0.69, p=0.03), as well as PBMC to whole blood AUC0-24
ratio (rS=-0.60, p=0.07). Tested ABCB1 genotypes
had no influence on cyclosporine pharmacokinetic parameters
in PBMCs and whole blood. The haplotypes investigated were
neither significantly correlated with PBMC ABCB1
mRNA expression nor with P-gp activity in CD4+
and CD8+. In conclusion,
cyclosporine PBMC pharmacokinetics was influenced by P-gp
activity and cyclosporine whole blood concentrations did not
predict PBMC drug levels, suggesting that despite values in
the therapeutic range, some subjects could have inadequate
intracellular drug levels.
[Back to top]
Synthesis and Evaluation of Macromolecule-Bound Derivative
of a Peptidyl-1-β-D-arabinofuranosylcytosine
Prodrug
Zoltan Balajthy
Macromolecule-bound Val-Leu-Lys-ara-C (1)
prodrugs were synthesized with spacers (-HN-(CH2
)x -CO-; x =1,3,5) between
the dextran carrier (T-70) and 1, in order
to achieve a sustained-release drug delivery system dextran-NH-(CH2)
x :1,3,5-CO-Val-Leu-Lys-ara-C
(5, 6 and 7).
The conjugation increased the stability of 1
in aqueous buffer solutions by three times (t1/2 53.0 h, pH
7.4). The length of spacer also regulated the rate of hydrolysis
of the prodrugs in serum. The shortest spacer (-HN-(CH2)-CO-,
(2)) in 5 provided the best protection of 1
against the hydrolyzing ability of proteinase- α2-macroglobulin
complexes, increasing its half-life approximately 30-fold.
The conjugation procedure resulted in a growth arrest ability
for macromolecular-bound prodrugs 5, 6
and 7 against L1210 with IC50
of 0.01 μM
in vitro, which is significantly lower than that
of other ara-C-macromolecule conjugates. 5
and 6 arrested cell growth in a broader range
of concentration, between 1 * 10-5
-1.0 μM,
than ara-C could.
[Back to top]
Brain-to-Plasma Distribution Ratio of the Biflavone Amentoflavone
in the Mouse
Milena Colovic, Claudia Fracasso and Silvio Caccia
Amentoflavone crosses the blood-brain barrier in
vitro but did not inhibit benzodiazepine binding in
vivo suggesting poor brain permeability. This prompted
us to examine its brain distribution in mice. After Hypericum
perforatum and Gingko biloba extracts its brain
concentrations were below the limit of quantification. Levels
were consistently detected only after intraperitoneal amentoflavone
(10 mg/kg), with mean brain-to-plasma ratio of about 0.02.
These concentrations were possibly related to the compound’s
contribution from residual blood, but in any case are too
low to support any interaction with central mechanisms so
far tested.
[Back to top]
The Effects of the 3,4-Methylenedioxymethamphetamine (Ecstasy)
in Some Cerebral Areas: Role of the Oxidative Stress
Sergio Franzese and Anna Capasso
The purpose of the present review is to examine the effect
of the acute administration (20 mg/ Kg, i.p.) of the 3,4 methylenedioxymethamphetamine
(MDMA) in different cerebral areas of rats to better understand
the mechanism underlying the toxicity induced by cellular
oxidative stress. For this purpose the biochemical parameters
of the antioxidant non-enzymatic cellular defense system have
been studied (the reduced Glutathione (GSH), the Glutathione
Disulfide (GSSG), the Ascorbic Acid (AA) and malondialdehyde
(MDA) which indicates perioxidative damage) in the hippocampus,
striate, frontal cortex both in treated animals and in control
groups to realize a qualitative-quantitative evaluation of
the possible alterations of the neuronal redox state induced
by the administration of Ecstasy.
The administration of MDMA induced the following variations
of the antioxidant non enzymatic defense system:
1. the levels of the AA in the treated animals compared with
the control group were increased in the striate, hippocampus
and in the frontal cortex both at 3h and 6h.
2. In the striate, also MDA was significantly increased both
after 3 h and 6 h, while in the hippocampus and in the frontal
cortex the MDA was significantly increased after 6 h.
3. An increase of GSH was also observed after 3 h and 6 h
in the hippocampus and in the striate while no significative
variation were observed in the frontal cortex of the treated
rats.
4. An increase of GSSG was significative in the hippocampus
and striate at 3h, while at 6h it was significative only in
the striate.
In conclusion the results of our study seem to confirm the
role of the oxidative stress in the mechanism of neuronal
toxicity induced by the ecstasy and leads us to hypothesize
a possible role of the antioxidant substances in the therapeutic
treatment of the intoxicants by MDMA.
[Back to top]
Analysis of Flavin-Containing Monooxygenase 3 Genotype Data
in Populations Administered the Anti-Schizophrenia Agent Olanzapine
John R. Cashman, Jun Zhang, Matthew R. Nelson and Andreas
Braun
Flavin-containing monooxygenase 3 (FMO3) genotype
data for European-, Latin-, African- and Asian-American schizophrenia
patients administered olanzapine were compared to age-, gender-,
and race/ethnicity-matched controls. Single nucleotide polymorphisms
and haplotypes associated with case-control status was undertaken
to determine the potential role of FMO3 in olanzapine
therapeutic response. The relationship between side effects
and FMO3 genotype and allele frequencies was also
studied. For European Americans, significant differences in
individual cases versus controls were observed between FMO3
158 and 257 alleles and genotype frequencies and schizophrenia
delusions, hallucinations, and weight gain/increased appetite
but this was not observed in a replicated population. For
Latin Americans, a significant difference in individual cases
versus controls was observed for FMO3 158 and 257
for schizophrenia delusions as well as hallucinations and
delusions. Sleepiness and weight gain was associated with
allele 308. In African Americans, a comparison of allele frequency
and diagnosis showed a significant dependence on allele 158
in individual cases versus controls. FMO3 genotype
and allele frequency was not significantly associated with
auditory hallucinations or delusions. For Asian Americans,
no significant difference in allele or genotype frequency
and auditory hallucination and delusions was observed in individual
cases versus controls. In female Asian American, allele frequency
for FMO3 257 was significantly associated with diagnosis
and in males, genotype frequency for FMO3 257 and
diagnosis was significantly associated.
[Back to top]
Effect of Folic Acid on Methotrexate Induction of Sulfotransferases
in Rats
Sangita Maiti Dutta, Smarajit Maiti and Guangping Chen
Our earlier investigation showed that MTX is an inducer
of rat and human sulfotransferases. Here we report that folic
acid treatment inhibited MTX induction of aryl sulfotransferase
(AST-IV) in female rat liver and hydroxysteroid sulfotransferase
(STa) in male rat liver. This is important for understanding
the clinical mechanisms of MTX.
[Back to top]
The Use of 1-Aminobenzotriazole in Differentiating the Role
of CYP-Mediated First Pass Metabolism and
Absorption in Limiting Drug Oral Bioavailability: A Case Study
Ayman F. El-Kattan, Julie Poe, Lisa Buchholz, Hayden V.
Thomas, Joanne Brodfuehrer and Alan Clark
Preliminary studies in our laboratory demonstrated low
oral bioavailability of Drug X in male Sprague Dawley rats.
However, the factors responsible for the observed poor bioavailability
were not well understood. The objective of this study was
to investigate the contribution of cytochrome P450(s) metabolism
to the observed poor oral bioavailability of Drug X in male
Sprague-Dawley rats in the presence of 1-aminobenzotriazole,
a non-specific irreversible inhibitor of cytochrome P450s.
Male Sprague-Dawley rats were pre-treated with or without
oral 1-aminobenzotriazole (50 mg/kg) two hours prior to receiving
a single intravenous or oral dose of Drug X (3 mg/kg). Blood
samples were collected from animals at different time points
over six hours following Drug X dosing. Plasma concentrations
of Drug X were determined using LC/MS/MS. Pharmacokinetic
data obtained from an intravenous dose study in rats suggested
that Drug X exhibited a high clearance (55 mL/min/kg) and
moderate volume of distribution (1.3 L/kg) with short half-life
in rats (0.7 hr). Oral dosing of Drug X to rats resulted in
low oral bioavailability (19%). 1-aminobenzotriazole pre-treatment
of male Sprague Dawley rats followed by an intravenous dose
of Drug X resulted in a decrease in plasma clearance by 71%
and an increase in half-life by 100%, without affecting the
volume of distribution. Furthermore, the oral bioavailability
of Drug X increased markedly with 1-aminobenzotriazole pre-treatment.
However, the fraction absorbed of Drug X did not significantly
change with 1-aminobenzotriazole pre-treatment. The results
of this study indicated that CYP-mediated metabolism played
a major role in limiting the oral bioavailability of Drug
X in rats. The data suggests that 1-aminobenzotriazole can
be used as an effective tool in assessing the factors contributing
to the poor oral bioavailability of drugs.
[Back to top]
Stability of Methadone and Its Main Metabolite in Oral Fluid
Nadia Fucci and Nadia De Giovanni
Saliva is a readily available specimen that can be collected
by non-invasive procedures and contains many drugs of interest
in screening and diagnosis. It is obtained by a painless and
non invasive method of sampling; it contains the free fraction
of drugs and therefore it is a good indicator of intoxication
state.
Inspite of its usefulness, only a few studies on long-term
storage have been conducted for some drugs of abuse, while
methadone stability have not been investigated yet. This lack
in standardization and the scarcity of analytical protocols
ac-tually restrict saliva applications.
Authors studied methadone stability on saliva during 12 months.
Fifty-nine saliva samples were collected from heroin addicts
in methadone treatment with the Cozart Rapiscan Collection
procedure.
The samples, spiked with tri-deuterated internal standards
analogs of methadone and 2-ethyl-1,5-dimethyl-3,3-diphenyl-pyrrolinium
perchlorate (EDDP), were submitted to Solid Phase MicroExtraction-Gas
Chromatography/Mass Spectrometry (SPME-GC/MS) technique.
Quantitative determinations of methadone and EDDP were performed
immediately and after various intervals (one month, two months,
twelve months). The results obtained from this experiment
show that methadone is sufficiently stable at 4°C until
2 months, while a decrease have been observed for EDDP.
These preliminary data prove the need to perform the analysis
in a brief time, to avoid loss of EDDP. For the correct use
of this biological matrix, more research and guidelines are
recommended for drug testing on saliva.
[Back to top]
Quantitative Structure-Retention-Pharmacokinetic Relationship
Studies
Snezana Agatonovic-Kustrin, Joseph V. Turner and Beverley
D. Glass
Since the majority of lead compounds identified for drug
clinical trials fail to reach the market due to poor efficacy
in humans or poor pharmacokinetics (PKs), the prediction of
PK properties in humans plays an important role in selection
of potential drug candidates. The aim of the present study
was to develop novel models for the prediction of separate
PK parameters for a diverse set of drugs. Prediction would
be based on the retention of each drug using micellar liquid
chromatography (MLC) and selected theoretically-derived descriptors.
Retention time, half life (t1/2),
and volume of distribution (Vd) for each of the 26 training
drugs were extracted from literature while molecular descriptors
were generated using Molecular Modeling Pro. A total of 35
molecular descriptors describing molecular size, shape and
solubility were calculated from the 3D molecular structure
of each compound. Artificial neural network (ANN) modeling
was used to correlate the calculated descriptors and retention
time with half life and volume of distribution. A sensitivity
analysis procedure was used to refine the models.
The final predictive models showed significant correlations
with literature values of t1/2
and Vd: 0.854 and 0.855 respectively for the internal testing
data and 0.720 and 0.827 respectively for the external validation
set of compounds. Absolute predicted values were in good agreement
with literature values. Analysis of descriptors in the optimum
models revealed a large degree of overlap. Solubility characteristics,
hydrogen bonding, and molecular size and shape were shown
to play important roles in determining drug t1/2
and Vd. The reciprocal of retention time was also included
in both optimum models attesting to the significance of this
particular physicochemical parameter and the complexity of
the models developed.
This novel combination of theoretical and experimental data
for pharmacokinetic modeling may lead to further progress
in drug development.
[Back to top]
Long Term Treatment with Tetradecylthioacetic Acid Improves
the Antioxidant Status in Obese Zucker (fa/fa) Rats
Hege Wergedahl, Kjetil Berge, Pavol Bohov, Karl-Johan
Tronstad, Lise Madsen and Rolf K. Berge
Increased oxidative stress was observed in obese Zucker
rats. Treatment of obese rats with tetradecylthioacetic acid
for 12 weeks increased the H2 O2-production,
but decreased plasma malondialdehyde, changed the serum fatty
acid profile, increased liver fatty acid binding protein mRNA,
and lowered serum insulin, thereby enhancing the antioxidant
defense system.
[Back to top]
Pharmacokinetics and Metabolism of Diltiazem Following Multiple
Doses: Comparing Normotensive Rat vs Hypertensive
Rat Models In vivo
Pollen K.F. Yeung, Angelita Alcos, Jinglan Tang and William
L. Casley
In order to identify a suitable rodent model for preclinical
study of calcium antagonists, pharmacokinetics and metabolism
of diltiazem (DTZ) were compared in normotensive SD and hypertensive
SHR rat models following multiple doses (5 mg/kg twice daily
for 5 doses). Plasma concentrations of DTZ and its major metabolites
appeared to be higher in the SHR than the SD rats, although
the differences did not reach statistical significance (p
> 0.05). The preliminary results suggest metabolism profile
of DTZ in the SHR may be closer to humans than the SD rats
and may be more preferred in pre-clinical drug development
studies for DTZ.
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