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The delaware valley

The Delaware Valley
DRUG METABOLISM DISCUSSION GROUP
Thursday June 7, 2012
Sheraton Bucks County, Langhorne PA
The 2012 Rozman Symposium on:
I) Drug Metabolism Hot Topics
Non-CYP metabolism
Metabolite identification of non-radiolabeled substrates
II) Biologics
Morning session
Drug Metabolism

8:30 – 9:00 am

Registration

Session I

Hot topics: Non-CYP metabolism

9:00 – 9:40 am

The Role of Aldehyde Oxidase in Drug Metabolism
Donald and Marianna Matteson Professor of Chemistry
9:40 – 10:20 am
UGT2B17 Genetic Polymorphisms Dramatically Affect the
Pharmacokinetics
in Healthy Subjects in a First-
in-Human
Research Fellow, Dept of Pharmacokinetics, Pharmacodynamics
10:20 – 10:40 am
Coffee break

Session II

Hot topics: Metabolite identification of non-radiolabeled
substrates
10:40 – 11:20 am
Hot Results from Cold Compounds: Application of
Alternative
Analytical
Methods to Yield Excretion Balance
Information Without the Use of a Radiolabel

11:20 – 12.00
Metabolite Identification With Non-Radiolabeled Compounds:
the Good, the Bad, the Ugly
Novartis
12.00 – 2 pm
Poster session* Titles listed below

12:00 – 2 pm


Afternoon session

Biologics

2:00 – 2:40 pm

In Vitro Assessment of Biologics DDI

2:40 – 2:50 pm
Coffee break

2:50 – 3:30 pm

A Platform PBPK Model for Biologics

3:30 – 4:10 pm
Challenges and Opportunities in Therapeutic Protein-Drug
Interaction
Assessments - A Perspective from
Head of Pharmacokinetics & Pharmacometrics *Posters

1) Cocktail Approach for Screening Relatively Selective UGT Inhibitors from
the Chemical SampleBank.
Arti Mathur*, Chuan Bai, Donald Tweedie, and Yongmei Li
Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc.
2) Differential Selectivity of Efflux Transporter Inhibitors in Caco-2 and MDCK-
MDR1 Monolayers: A Strategy to Assess the Interaction of a New Chemical Entity
with P-gp, BCRP and MRP2.
Kirsten Mease, Rucha Sane, Lalitha Podila*, and Mitchell E. Taub
Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc.
3) The Impact of FcRn on Tissue Distribution of IgG1 in Mice
Nancy Chen, Weirong Wang, Scott Fauty, Yulin Fang, Ping Lu, Lora Hamuro, Azher
Hussain and Thomayant Prueksaritanant, Merck
4) In vitro Evaluation of Regional Differences in Active Drug Transport and
Metabolism in Rat and Human Intestine
Wang, X., Guerra, F., Joseph, J., Huang, Y., Zhang, W., Bhoopathy, S. and Hidalgo, I.,
Absorption Systems
5) Determination of Efflux Transporter Membrane Location using Caco-2
Knockdown Cells

Weiskircher EA, McLaughlin A, Miezeiewksi B, Wang Q, Bhoopathy S, Nagar S,
Korzekwa K, and Hidalgo, I., Absorption Systems
6) Identification of Novel Domperidone Metabolites in Human by LC-ESI-MS/MS
Amir Youssef¹, Murali Pathikonda², Upendra A. Argikar³, Henry P. Parkman² and Swati
V. Nagar¹
¹Department of Pharmaceutical Sciences, Temple University School of Pharmacy,
²School of Medicine, Temple University, Philadelphia, PA, ³Novartis Institutes for
Biomedical Research, Inc., Cambridge, MA
7) The Role of Aldehyde Oxidase in the Pharmacokinetics and Metabolism of
Anticancer Drug Candidates
Sarah Lawrence1, Liangfu Chen1, Peter Gorycki1, Charles Davis2, Konstantine Skordos1
1Department of Drug Metabolism and Pharmacokinetics, 2Department of Cancer
Metabolism: PreClinical Drug Discovery, GlaxoSmithKline. 709 Swedeland Road,
King of Prussia, PA 19406
8) Effect of Maternal Low Protein Diet During Pregnancy and Lactation on the
Activity of Liver, Muscle, and Heart Carnitine Palmitoyltransferase-1 Activity in
the Adult Offspring

Veron Browne1, Rani J. Qasem1, Elizabeth Yablonski1 , Jing Li1, Hee Man Tang1, Laura Pontiggia2, Anil P. D’mello1 1Department of Pharmaceutical Sciences; and 2Department of Mathematics, Physics, and
Statistics, University of the Sciences in Philadelphia, Philadelphia, PA, 19104.
9) Investigations into the Cytotoxicity of 3-(3,5-Dichlorophenyl)-2,4-
thiazolidinedione (DCPT) and its Metabolites in Human HepG2 Cells
Sadaff Ejaz, Ruy Tchao and Peter J. Harvison, University of the Sciences in Philadelphia,
Department of Pharmaceutical Sciences.
Presentation abstracts
The Role of Aldehyde Oxidase in Drug Metabolism
Jeffrey P. Jones
Aldehyde oxidase (AO), while not a major drug metabolizing enzyme, has become
increasingly important in drug failures in clinical trials and during development.
Screening for AO activity requires the use of a human enzyme source, since animals do
not represent the human condition. Screening should be done at multiple concentrations
since most substrates show substrate inhibition at high concentrations. Furthermore, a
number of drugs and natural products inhibit AO with almost all the drugs studied thus
far showing complex inhibition patterns. The good news (GN) is that most AO substrates
are also metabolized by other drug metabolizing enzymes. The bad news (BN) is that the
enzyme produces reactive oxygen species, and in the presence of nitrite AO can produce
large amounts of nitric oxide. Initial studies on known SNPs have shown only modest
variability with a number of substrates (GN), although a rare (?) human phenotype exists
that has no aldehyde oxidase activity (BN). Human liver cytosol and hepatocytes show
variability in activity from one batch to the next (BN) for reasons that are not clear but
appear to result from enzyme lability and poor cofactor incorporation. However, the GN
is that computational models appear to work rather well at predicting both the rates and
regioselectivity of AO metabolism. I will present new data on the inhibition of AO, the
possible range of activity in human livers, and show correlations between computational
models for intrinsic clearance and actual measured values.
UGT2B17 Genetic Polymorphisms Dramatically Affect the Pharmacokinetics of
MK-7246 in Healthy Subjects in a First-in-Man study
Y. Wang,1 M. Trucksis,1 J. McElwee,1 P. Wong,1 C. Maciolek,1 C. Thompson,1 T.
Prueksaritanont,1 C. Gibson,1 G. Garrett,1 R. Delercq,1 E. Vets,2 K. Willson,1 R. Smith,1
J. Klappenbach,1 G. Opiteck,1 J. Tsou,1 T. Laethem,1 P. Panorchan,1 L. Maganti,1 M.
Iwamoto,1 R. Rippley,1 P. Shaw,1 J. Wagner,1 J. Harrelson1; 1Merck & Co., Inc.,
Whitehouse Station, NJ, 2SGS Life Science Services, Antwerp, Belgium

BACKGROUND:
MK-7246 is an antagonist of chemoattractant receptor on Th2
(CRTH2) cells developed for the treatment of respiratory diseases. The objective of this
study was to investigate whether genetic polymorphism could contribute to the marked
inter-individual pharmacokinetic variability in MK-7246 and its glucuronide metabolite
(M3) observed in the MK-7246 first-in-man study.
METHODS: In vitro UGT studies were conducted to identify the UGT isoforms
responsible for MK-7246 glucuronidation. Subjects who participated in the first-in-man
study were genotyped. Dose-normalized area under the plasma concentration–time curve
(AUC) and peak plasma concentration (Cmax) values were determined, and genetic
association analysis was performed.
RESULTS: In vitro enzyme kinetic studies suggested that UGT2B17 had high affinity
for MK-7246, thus was likely the major enzyme responsible for MK-7246 metabolism in
both the liver and intestine. Compared with the UGT2B17*1/*1 wild-type genotype,
UGT2B17*2/*2 individuals, who possess no UGT2B17 protein, had 25- and 80-fold
greater mean dose-normalized AUC and Cmax of MK-7246, respectively; and a 24-fold lower M3 to MK-7246 AUC ratio. The apparent half-life of MK-7246 was less variable
between these two genotypes. Pharmacokinetics of MK-7246 was similar among subjects
with at least one UGT2B17*1 allele.
CONCLUSION: The genetic analysis confirms that UGT2B17 enzyme is the major
UGT enzyme responsible for the glucuronidation of MK-7246. UGT2B17 genetic
polymorphisms are associated with highly variable pharmacokinetics of MK-7246
observed in the FIM study. The substantial effects of UGT2B17 polymorphism suggest
that the potential effect of a potent inhibitor of UGT2B17 on a concomitant specific
UGT2B17 substrate can not be ignored. UGT phenotyping should be performed when a
compound is primarily eliminated by glucuronidation to dial out potentially serious drug
interactions or large variability in pharmacokinetics.
Hot Results from Cold Compounds: Application of Alternative Analytical Methods
to Yield Excretion Balance Information without the Use of a Radiolabel

William M. Hardesty, Igor Goljer, Janine M. Rogers, Caroline Sychterz, Ernest M.
Schubert, GlaxoSmithKline, King of Prussia PA
Pre-clinical mass balance studies using radiolabel have been standard in the drug
development process. However, given the high attrition rates of drug candidates, the
choice to delay the radiolabel synthesis until later in drug development process represents
a viable cost savings. This talk will describe how the ultraviolet (UV) chromophore and
trifluoro methyl moiety of a drug candidate were both exploited to yield mass balance
and biotransformation information from a preclinical rat ADME study before
commitment to radiolabel production. The benefits and drawbacks of both UV
spectrophotometry and fluorine-19 nuclear magnetic resonance (19F NMR) spectrometry
as quantitative analytical tools will be addressed. The impact of the data on early clinical
development plans for the asset will also be discussed.
Metabolite Identification studies with non-radiolabeled compounds: the good, the
bad, the ugly
Upendra A. Argikar
Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue,
Cambridge, MA 02139
The presentation will cover newer technologies as applied to metabolite identification
studies with non-radiolabeled chemical entities. Application of higher energy collisional
activation cell in order to enhance precursor ion fragmentation will be exemplified. In
addition fragment based analysis of comparative in silico and in vitro biotransformation
data from approximately 70 new chemical entities, aimed at gaining a deeper
understanding of metabolite prediction software (MetaSite®) will be discussed. Finally,
interesting aspects of metabolite quantification by ESI mass spectrometry in early drug
discovery will be presented in the form of a case study.


In Vitro Assessment of Biologics DDI
Larry Wienkers
The cytokine-mediated suppression of hepatic drug metabolizing enzymes by
inflammatory disease and the relief of suppression (“de-suppression”) by successful
disease treatment has become an important feature in the development of drug interaction
labels for new biological products. In the past year, it has been proposed that in vitro
information for cytokine-modulating biologics could be generated to help context and
perhaps predict the likelihood of these types of Drug-Drug Interactions occurring in the
clinic. In this presentation, P450 suppression and de-suppression studies on IL-6 in
primary hepatocyte culture and studies using the murine collagen antibody-induced
arthritis (CAIA) model will be used to probe the magnitude of P450 changes incurred by
treating inflammatory disease. Preclinical P450 suppression and desuppression data will
be compared to available preclinical & clinical literature to elucidate the pros and cons of
preclinical experimentation on this drug-disease interaction.

A Platform PBPK Model for Biologics
Dhaval K. Shah
The presentation will focus on the development of a physiologically based
pharmacokinetic (PBPK) model capable of characterizing the plasma and tissue
pharmacokinetics (PK) of nonspecific or antigen specific monoclonal antibodies (mAbs)
in wild type, FcRn knockout, tumor bearing and non tumor bearing mice. Scale up
potential of the model will be evaluated by characterizing the mouse, rat, monkey and
human plasma PK of mAbs, simultaneously. The model is able to characterize the plasma
PK of mAb in mouse, rat, monkey and human with a common set of estimated
parameters, whose values were close to some of the literature reported values. Apart from
mAbs the model may also be capable of characterizing other macromolecular modalities
without any major structural changes. Thus, a platform PBPK model has been developed
that can characterize the data from many previously published mAb PBPK models
simultaneously, and it provides a better alternative to over-parameterized two-pore
models and an augmentation to previously published single-pore models.
Challenges and Opportunities in Therapeutic Protein-Drug Interaction
(TP-DI) Assessments - A Perspective from IQ/DMLG - TP-DI Working Group
Honghui Zhou, PhD, Pharmacokinetics & Pharmacometrics, Biologics Clinical
Pharmacology, Johnson & Johnson
Therapeutic proteins (such as antibody-based therapeutic proteins) have become
increasingly more important in pharmacotherapy, and some of the therapeutic proteins
have stood out as therapies of choice for certain immune-mediated inflammatory diseases
and malignancies. Therapeutic proteins are commonly used concomitantly with other
drugs and a certain amount of clinically relevant information has begun to emerge on
drug-drug interaction potential of those therapies over the last several years.
Nevertheless, to investigate drug-drug interaction potential for a therapeutic protein is
inherently complicated and challenging. Some major gaps and challenges in assessing
therapeutic protein-drug interactions (TP-DIs) have been identified by a 2010 BIO TP-DI
Survey, AAPS TP-DI Workshop in 2010, and IQ/DMLG – TP-DI Working Group. This
presentation is intended to give a high-level summary of some ongoing activities in TP-
DI within IQ/DMLG – TP-DI Working Group as well as highlight the most recent
‘Workshop On Recent Advances In the Investigation of Therapeutic Protein Drug-Drug
Interactions: Preclinical and Clinical Approaches’ held on June 4 and 5, 2012.
Poster abstracts
1) Cocktail Approach for Screening Selective UGT Inhibitors from a Chemical
Sample Bank
Arti Mathur, Chuan Bai, Donald J. Tweedie, Yongmei Li
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, CT
One of the challenges to perform UGT phenotyping is the lack of selective inhibitors of
different UGT isoforms. By now, only a few selective inhibitors have been identified and
there is a need to discover more selective UGT inhibitors. An automated screening was
performed for 1000 compounds to identify potential selective inhibitors of UGT
enzymes. In order to screen a large number of compounds in a high throughput manner
and to accommodate a very limited volume (3.6 µL) of each compound, a novel UGT
probe cocktail approach was developed to measure enzyme activities of five major
hepatic UGT isoforms (UGT1A1, 1A3, 1A6, 1A9, and 2B15) in one assay. In this
cocktail assay, five specific UGT probes were incubated with human liver microsomes as
a combination. The effect of one probe on the activities of other UGT isoforms was
evaluated. In addition, a unique LC/MS/MS method was developed to quantitate
metabolites of all 5 UGT probes which significantly enhanced bioanalytical throughput.
This cocktail combination was used for the subsequent inhibitor screening assays. As a
result, 20 compounds were identified as promising selective inhibitors of the studied
UGT isoforms.

3) The Impact of FcRn on Tissue Distribution of IgG1 in Mice
Nancy Chen, Weirong Wang, Scott Fauty, Yulin Fang, Ping Lu, Lora Hamuro, Azher
Hussain and Thomayant Prueksaritanant

Purpose: FcRn plays a pivotal role in IgG homeostasis, where it salvages the antibody
from lysosomal degradation, preventing it from rapid systemic elimination. In addition to
its protective role in antibody clearance, a few studies had suggested that FcRn may also
play a role in tissue biodistribution of IgG. In this report, we investigated the impact of
FcRn on tissue distribution of human IgG1 in this KO model and wild type mice.
Methods: An 125I- labeled human IgG1 antibody was injected in both C57/BL6 and FcRn
KO mice. The radioactivity of the antibody in the plasma and tissues was measured by a
gamma counter. The concentration of the antibody in plasma was also analyzed by
ELISA. The integrity of the antibody in the liver was further determined by Western Blot.
Results: Plasma area under the curve (AUC) was significantly lower in the KO mice,
which is consistent with the primary function of FcRn. Furthermore, FcRn appeared to
have an increase in tissue to blood ratio in liver and spleen in a time-dependent manner in
the KO mice. In the bone and kidney, only at 72 and 96h there were significant
differences from the wild type animals. Western blot of liver lysate from the KO mice
suggested that the antibody is likely still intact throughout the studied time course.
Conclusions: These results suggest that in addition to its role in IgG elimination, FcRn
could also play a role in antibody biodistribution potentially through transcytosis across
the vasculature endothelial cells for some organs.

4)
In vitro Evaluation of Regional Differences in Active Drug Transport and
Metabolism in Rat and Human Intestine
Wang, X., Guerra, F., Joseph, J., Huang, Y., Zhang, W., Bhoopathy, S. and Hidalgo, I.,
Absorption Systems
The extent of intestinal absorption of many drugs are affected by active drug transporters
such as MDR1 P-glycoprotein (P-gp), proton-coupled oligopeptide transporter (PepT1),
and intestinal metabolic enzyme cytochrome P450 3A (CYP3A). The purpose of the
present study is to characterize and compare regional differences in the expression and
function of the membrane drug transporters P-gp, PepT1 and metabolic enzyme CYP3A
in isolated rat and human intestinal tissue to better mimic the in vivo environment.
Freshly excised duodenum, jejunum, ileum and colon from rats or human donors were
muscle-stripped and mounted on Ussing chambers. Bi-directional digoxin (10 μM)
permeability assays with and without the P-gp inhibitor cyclosporin A (CsA) were
performed to determine P-gp functionality. The expression of P-gp, PepT1 and CYP3A
mRNA was analyzed using qPCR to evaluate the concordance between expression and
function. The P-gp function in rat intestine is the highest in colon and ileum, followed by
jejunum and the lowest in duodenum. The presence of CsA induced a nearly complete
inhibition of digoxin efflux. A similar trend was observed in human intestinal epithelia,
with lower ERs than these in rat intestine. The mRNA expression of PepT1 decreased in
a distal direction, with the highest expression in human duodenum samples. The highest
level of expression of human CYP3A was found in jejunum, followed, in a decreasing
order, by duodenum, ileum and colon. In conclusion, the in vitro Ussing chamber
method can be used to study the expression and function correlations for intestinal P-gp,
PepT1 and CYP3A. The extent of affected drug transport in isolated rat or human
intestinal tissues could help predict the role of these processes in intestinal drug
absorption.

5)
Determination of Efflux Transporter Membrane Location using Caco-2
Knockdown Cells

Weiskircher EA, McLaughlin A, Miezeiewksi B, Wang Q, Bhoopathy S, Nagar S*,
Korzekwa K*, and Hidalgo, I., Absorption Systems and *Temple University
Transport of many drugs and endogenous compounds across cell membranes is known to
be controlled by efflux transporter proteins. Since efflux transporters play an important
role in maintaining homeostasis and protecting the body from xenobiotic compounds, it
has been suggested that these transporters may work in concert to elicit the transport of
compounds out of the cell. Based on their specific location within the membrane these
transporters can act in parallel or sequentially: if both transporters are located either on
the cytoplasmic membrane or inside the hydrocarbon domain of the lipid bilayer, they are
expected to act in parallel and, but if one is located on the cytoplasmic membrane while
the other is on the hydrocarbon domain, they are expect to act sequentially. In parallel
transport, the transporters are both acting to efflux the compounds; if either transporter
level is reduced, the sister transporter can act to decrease the resulting adverse effects.
As an example, it has been demonstrated, in vivo, that knockout of both efflux
transporters, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), at the
blood brain barrier resulted in a synergistic, not additive, effect on the disposition of the
compound1. In the case of sequential efflux, a compound may be taken up from the
cytosol by a transporter such as Multidrug Resistance-associated Protein 2 (MRP2) and
delivered to the hydrocarbon domain (intramembrane space), where it is now able to
interact with a transporter located there, resulting in the efflux of the compound from the
cell. In this study, we aimed to determine the membrane location of three efflux
transporter proteins: P-gp, BCRP, and MRP2. Through the use of monolayers of Caco-2
cells and Caco-2 cells in which P-gp, BCRP or MRP2 were knocked down, we assessed
the effect of transporter suppression of the permeability of compounds known to be P-
gp/BCRP or BCRP/MRP2 substrates. In this study we have evaluated the hypothesis that
the extent to which the efflux of a compound, known to be substrate of two transporters,
is decreased when one of the transporters is knocked down suggests the location of the
transporters in relation to each other. Additionally, we suggest that, for compounds that
are substrates of a pair of efflux transporters, the affinity and/or specificity of the
interaction with a transporter can dictate the ability of the cell to extrude the drug
effectively in the absence of the other transporter.
6) Identification of Novel Domperidone Metabolites in Human by LC-ESI-MS/MS
Amir Youssef¹, Murali Pathikonda², Upendra A. Argikar³, Henry P. Parkman² and Swati
V. Nagar¹
¹Department of Pharmaceutical Sciences, Temple University School of Pharmacy,
²School of Medicine, Temple University, Philadelphia, PA, ³Novartis Institutes for
Biomedical Research, Inc., Cambridge, MA
Purpose: Domperidone is a dopamine type 2 receptor antagonist that is used as a
prokinetic agent to treat gastroparesis. After oral absorption, it is extensively metabolized
in the liver. Previous studies reported oxidative metabolites of domperidone, detected by
radiometric-HPLC or single quadrupole mass spectrometric (LC-MS) techniques. Our
aim was to identify domperidone ‘phase I’ (oxidation/reduction) and ‘phase II’
(conjugation) metabolites with liquid chromatography (LC) and tandem mass
spectrometry (MS/MS).
Methods: Gastroparesis patients (n= 11, 18-65 years old) currently being treated with
domperidone at a dose of 10 or20 mg 3-4 times/day were recruited. Subjects were non-
smokers and were not on other medications known to be substrates, inducers or inhibitors
of cytochrome P450 (CYP) 3A4. At the start of the study, an initial urine sample was
collected. Patients were then administered their usual domperidone dose. A blood sample
was collected one hour after the dose. Urine was collected (entire volume collection) for
4 hours post-dose. All blood and urine samples were stored immediately upon collection
at −20°C until further analysis. In vitro incubations were performed in human liver
microsomes (HLM) and recombinant purified CYP3A4 to characterize metabolism
mediated by CYPs and UDPglucuronosyltransferases and in human liver cytosol for
metabolism via sulfotransferases. Metabolite identification studies were carried out using
LC- MS/MS.
Results: Seven metabolites were detected in human plasma and urine samples.
Domperidone was metabolized to two mono-hydroxylated metabolites (M1,M2), a de-
alkylated metabolite (M5), and a di-hydroxylated metabolite (M7). M1 was further
glucuronidated and sulfated to M8 and M11 respectively. To the best of our knowledge,
M7, M8, and M11 have not been reported previously. Six additional metabolites were
identified in vitro in human subcellular fractions which comprise two additional mono-
hydroxylated metabolites (M3, M4), an alcohol metabolite (M6) possibly formed from an
aldehyde intermediate, and other conjugative metabolites (M9, M10 and M12).
Conclusion: In total, 12 domperidone metabolites including 6 new metabolites have been
identified. Furthermore, M1 to M7 were identified in CYP3A4 incubations indicating that
it contributes to domperidone metabolism. These results will ultimately allow a better
understanding of domperidone disposition in-vivo in humans.
7) The Role of Aldehyde Oxidase in the Pharmacokinetics and Metabolism of
Anticancer Drug Candidates

Sarah Lawrence1, Liangfu Chen1, Peter Gorycki1, Charles Davis2, Konstantine Skordos1
1Department of Drug Metabolism and Pharmacokinetics, 2Department of Cancer
Metabolism: PreClinical Drug Discovery, GlaxoSmithKline. 709 Swedeland Road,
King of Prussia, PA 19406
Abstract:
Two compounds in development in the oncology therapeutic area, bearing similar
structural cores, had pronounced differences in human pharmacokinetics (exposure).
Investigative studies in human liver microsomes identified an NADPH independent
metabolite. Studies in hepatic S9 and cytosol fractions in the absence and presence of
menadione as well as metabolite structure, implicated the involvement of aldehyde
oxidase (AO) in the metabolism of both compounds. However, the comparative
metabolic rates revealed that the AO product’s formation was approximately 30-fold
higher for the compound which exhibited poor exposure in humans. We propose that AO
mediated metabolism was likely responsible for the poor exposure observed in the clinic.
Additional investigative studies using a methylated (blockade of AO metabolism) analog
of the compound further demonstrated the involvement of AO.
8) Effects of maternal low protein diet during pregnancy and lactation on the
activity of carnitine palmitoyltransferase-1 in liver, muscle, and heart of the adult
offspring

Veron Browne1, Rani J. Qasem1, Elizabeth Yablonski1 , Jing Li1, Hee Man Tang1, Laura
Pontiggia2, Anil P. D’mello1
1Department of Pharmaceutical Sciences; and 2Department of Mathematics, Physics, and Statistics, University of the Sciences in Philadelphia, Philadelphia, PA, 19104.
Maternal low protein diet during pregnancy and lactation decreased liver triglyceride
content in the adult male offspring. This decrease could be due to increased lipid
utilization caused by increased oxidation of free fatty acids. The objective of the current
study was to assess the status of fatty acid oxidation in the liver, heart, and muscle of 65
day old male control (C) and low protein (LP) offspring. The activity of carnitine
palmitoyltransferase-1 (CPT-1), a rate limiting enzyme in fatty acid oxidation, was used
to assess the status of fatty acid oxidation. The activity of CPT-1 was measured in the
forward direction using a spectrophotometric method to quantitate the CPT-1 catalyzed
and carnitine dependent rate of formation of acetyl coenzyme A from palmitoyl-CoA. LP
offspring exhibited a higher liver CPT-1 activity [14.3±1.52 (mean + S.D. n = 9-10)
nmol/min/mg mitochondrial protein] compared to C offspring [12.3±1.83 nmol/min/mg
mitochondrial protein]. There were no differences in CPT-1 activity between C and LP
offspring in muscle [C: 16.2±2.1; LP: 16.4±1.3 nmol/min/mg mitochondrial protein] and
heart [C: 18.9±1.9; LP: 18.2±1.9 nmol/min/mg mitochondrial protein]. Our results
suggest that maternal low protein diet specifically increases hepatic fatty acid oxidation
in the adult male offspring.

9) Investigations into the Cytotoxicity of 3-(3,5-Dichlorophenyl)-2,4-
thiazolidinedione (DCPT) and its Metabolites in Human HepG2 Cells.
Sadaff Ejaz, Ruy Tchao and Peter J. Harvison, Department of Pharmaceutical Sciences,
University of the Sciences in Philadelphia, Philadelphia, PA.
The thiazolidinedione (TZD) ring has been implicated in the hepatotoxicity of
troglitazone and similar drugs used to treat type II diabetes. We previously showed that
another TZD derivative, 3-(3,5-dichlorophenyl)-2,4-thiazolidinedione (DCPT), is
cytotoxic in HepG2 cells. DCPT can be converted into [[(3,5-
dichlorophenyl)amino]carbonyl]thioglycolic acid (DCTA), which could further degrade
into 3,5-dichlorophenyl isocyanate (DPI). DCTA and DPI may contribute to DCPT
toxicity. HepG2 cells were therefore treated with 200 µM DCPT, DCTA or DPI for up to
24 hr. We found that cell death was time-dependent and the earliest onset occurred with
DCTA. Furthermore, DCTA was significantly more cytotoxic than DCPT or DPI, and
produced a 67% loss of cell viability at 24 hr. In contrast, cell viability was reduced 47%
and 27% by DCPT and DPI, respectively. Intracellular glutathione (GSH) levels were
also measured for up to 8 hr. Only DCTA produced a significant decrease in GSH
content. Thus, it appears that DCTA may contribute to DCPT-induced cytotoxicity in
HepG2 cells. Furthermore, GSH depletion may be a factor in DCTA cytotoxicity.
Additional experiments are needed to understand the mechanism of cytotoxicity of DCPT
and its metabolites. Supported by PHS grant ES012499 and the USciences
Pharmaceutical Sciences Department.
Speaker biographies
Jeffrey P. Jones, Ph.D.
Dr. Jones is The Donald and Marianna Matteson Professor of Chemistry at Washington
State University. At present his main interests are in understanding nitrogen-iron
coordination effects on binding and metabolism by cytochrome P450, and structure
function and SNP characterization of human aldehyde oxidase. He was an Associate and
Assistant Professor in the Departments of Pharmacology, Physiology, Biochemistry and
Biophysics at the University of Rochester from 1987 through 1998 where he developed
predictive models for P450 binding and metabolism. He was a postdoc in the
Biochemistry Department at the University of Wisconsin from 1990-1992, where he
worked on the mechanism of phosphoryl transfer in Professor W.W. Cleland's lab. He
obtained his Ph.D. in the Department of Medicinal Chemistry at the University of
Washington from Professor William Trager, studying the mechanism of P450 mediated
oxidations. His B.S. is in Medicinal Chemistry from the University of Michigan. Dr.
Jones is co-inventor, With Dr. Ken Korzekwa, of the technology licensed to Camitro
Corporation for modeling human metabolism.
Ying-Hong Wang, Ph.D.
Ying-Hong Wang is a Research Fellow in the Department of Pharmacokinetics,
Pharmacodynamics & Drug metabolism at Merck Research Laboratory in West Point,
PA. She received her B.S. in Biochemistry from Nankai University in China, her Ph.D. in
Molecular and Cellular Biology from Oregon Health Sciences University, Portland, OR.
She joined Merck & Co., Inc. in 2004 after she completed her post-doc and Clinical
Pharmacology Fellowship Training with Dr. Stephen Hall from Indiana University-
Purdue University at Indianapolis. Her major interests are drug-drug interactions,
pharmacogenetics, and pharmacokinetics/pharmacodynamics. She has authored and co-
authored 14 manuscripts and 18 abstracts in these areas.

Ernest Schubert
Ernie Schubert received his M.S. in Chemistry from Emory University in 1994. He has
spent his entire career as an analytical chemist in the pharmaceutical industry with an
emphasis on the structure elucidation of small organic molecules using Nuclear Magnetic
Resonance (NMR) spectroscopy. He has spent the last 8+ years in the Drug Metabolism
and Pharmacokinetics department at GlaxoSmithKline, King of Prussia, PA, where he
currently co-manages the structure identification group.
Upendra A. Argikar, Ph.D.
Upendra Argikar is a Research Investigator in the Metabolism and Pharmacokinetics
Department at the Novartis Institutes for Biomedical Research, Inc. (NIBRI), in
Cambridge, MA. He received a Ph.D. in medicinal chemistry in 2006 from the University
of Minnesota, Twin Cities. He joined NIBRI in 2006 with a research focus on
biotransformation and pharmacokinetics of new chemical entities, pre-clinical and
clinical drugs. For the past several years his interests have also included conjugative
metabolism by human Uridine Glucuronosyl Transferase enzymes (UGTs), a topic on
which he has co-authored three book chapters. He has published several research articles and
serves as a reviewer for many scientific journals. He teaches drug metabolism at DMPK
courses across NIBRI sites and serves as a guest faculty at Massachusetts Institutes of
Technology (MIT), Cambridge, MA.
Larry Weinkers, Ph.D.
Larry C. Wienkers received his M.S. in Organic Chemistry from Western Washington
University in 1988 and a Ph.D. in Medicinal Chemistry from University of Washington
in 1993. Larry's current research interests are focused on exploring bioactivation
pathways associated with small molecule drug metabolism with particular focus on the
prospective application of this information to predict drug-drug interactions in the clinic.
To this end, his group applies a multidisciplinary approach using organic chemistry,
biochemistry and biophysical techniques to study cytochrome P450 mechanism based
inhibition and the characterization of biotransformation pathways of novel therapeutics.
Dhaval Shah, Ph.D.
Dr. Dhaval Shah is a Senior Scientist in the PK/PD modeling and simulation group at
Pfizer inc. He received his Ph.D. in Pharmaceutical Sciences from the State University of
New York at Buffalo in 2010. He is the recipient of the outstanding manuscript in
modeling and simulation award by AAPS in 2009, Graduate Student Symposium in
PPDM-CPTR Award by AAPS in 2010, and several Individual Performance awards by
Pfizer. His research interests involve development and application of mechanism-based
compartmental and systems pharmacology models to predict human PK/PD from
preclinical data. He is also interested in using PK/PD principles to help guide the
discovery and development of new biotherapeutics.
Honghui Zhou, Ph.D.
Dr. Zhou is a Senior Director at Biologics Clinical Pharmacology at Janssen Research &
Development of Johnson & Johnson where he is leading the Pharmacokinetics and
Pharmacometrics Group for therapeutic biologics. He received his Bachelor degree in
Pharmacology from China Pharmaceutical University and PhD degree in Pharmaceutics
from the University of Iowa. Honghui is board certified by American Board of Clinical
Pharmacology. Besides Johnson & Johnson, Honghui has also worked for Wyeth (now
Pfizer) and Novartis.
Honghui has (co)-authored many scientific manuscripts in the areas of clinical
pharmacology, therapeutic protein drug development,
pharmacokinetics/pharmacodynamics, and drug-drug interaction. He has been an invited
speaker in many national/international scientific conferences. He has been a Fellow at
American College of Clinical Pharmacology (ACCP) since 1999, and is currently serving
in the Board of Regents of ACCP (2009-2014). Honghui currently also serves as Section
Editor for Biologics for the Journal of Clinical Pharmacology. He also co-chairs
Industry/FDA/Academia Therapeutic Protein-Drug Interaction Steering Committee. In
addition, he has adjunct professor appointment in College of Pharmacy, the University of
Iowa.

Source: http://www.dvdmdg.org/Rozman%202012%20Agenda.pdf

Actos de navarra del borme núm. 183 de 2012

BOLETÍN OFICIAL DEL REGISTRO MERCANTIL Núm. 183 Viernes 21 de septiembre de 2012 Pág. 42176 SECCIÓN PRIMERA Empresarios 387222 - TINTORERIA SAN JUAN-BAZTAN SL. Declaración de unipersonalidad. Socio único: QUICK SEC IRUÑA SL. Ceses/Dimisiones. Adm. Solid.: CIA LAZCOZ ALFONSO CARLOS;CIA LAZCOZ JOAQUIN;CIA LAZCOZ RAMON TOMAS. Nombramientos. Adm. Unico: ELIZALDE USEC

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3.3 Statistically significant z scores for responses to Question 3 College A College B University C University D University E University F Residence halls (Note 1) #1: Collaborative learning#2: Studying alone#4: Discussing material with other students#5: Discussing material with faculty members#6: Working with faculty on non-course activities#7: Research outside

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