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Pharmacokinetics and Metabolism
MDS offers extensive capabilities to conduct pharmacokinetic evaluations and
analyses in animals. These in-life studies provide information for selection of:
dose levels
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Dosing frequency,
Formulation,
Routes of administration,
Exposure,
Interspecies comparisons.
Metabolism Assays NH
start a code for tox and chane the numbers
In vitro assays for human drug metabolism. Using human tissue in vitro metabolism and
absorption studies as key features of the drug discovery and development process.
Our study directors are available to assist with development of study designs and
data interpretation. We conduct your studies in a GLP environment, while
applying our experience and knowledge to your particular ADME problem to
move your drug or vaccine efficiently through the development process.
In Vivo ADME Studies
Absorption, Distribution, Metabolism and Excretion (ADME) studies are a vital part of the
comprehensive safety evaluation of a new chemical entity. MDS offers ADME studies in
small animals, using radio-labeled materials, that you provide or MDS synthesizes for
you. Routes of administration include oral, intravenous, dermal, intraperitoneal,
inhalation, intrathecal, and infusion as well as other intended delivery methods for your
compound These in-life studies provide information for:
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Metabolite isolation and characterization
Bioavailability evaluations
Bioequivalence studies
Formulation screening and optimization
Dosing frequency
Formulation,
Routes of administration,
Exposure,
Interspecies comparisons.
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In Vitro Absorption and Metabolism Models
In vitro models to predict drug absorption and
metabolism are valuable techniques for both
screening new drug candidates, and later
evaluations of potential drug-drug interactions. MDS
offers the following services:
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Predict gastrointestinal absorption,
using Caco2 cells.
 Rapid screening in multi well plates to
detection, to quickly identify those
compounds that can cross the GI tract
into the blood stream.
 Mechanism studies, evaluating flux
rate and permeability constants from the apical to basolateral, and
basolateral to apical directions
Evaluate drug metabolism and drug interactions, using human and
animal tissue models, such as primary hepatocytes.
Determine the metabolite profile of drug candidates using
hepatocytes, liver and small intestine microsomes and S9,
microsomes containing a single enzyme.
Predict drug interactions due to inhibition or induction of drug
metabolizing enzymes.
Identify pharmacogenetic effects on human drug metabolism
Study the transport properties of your drug, using bile canalicular
membrane vesicles from animals and humans.
Pharmacokinetics/ADME Studies
P101 Material Balance or Accountability Study*
The objective of this study is to investigate the excretion rate and tissue distribution
of the chemical.
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Groups of 5 male and 5 female rats at a single dose level
Daily collection of urine and feces for 7 days
Collect blood and major internal organs, and retain carcass upon necropsy
Total radioactivity level in each sample is assayed and the recovered dose is
compared with the administered dose. The percentage of distribution of the
administered dose in urine, feces, and each major internal organ and the halftime for excretion are calculated.
P101-R Optional Studies
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Analysis of CO2 in expired air
Analysis of injection site (e.g., if the dosing route is percutaneous or
intramuscular)
Two dose levels instead of one
Species other than rats (e.g., rabbits)
Repeated-dose study (unlabeled compound is administered daily for 13 days; on
the 14th day a radioactive dose is administered)
Major metabolites - isolation, characterization
P102 Plasma Level and Bioavailability Study*
The objective of this study is to examine the pharmacokinetic profiles of the chemicals
under test.
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These studies can be conducted by using unlabeled chemicals provided that
appropriate analytical procedures (e.g., HPLC) are available.
Groups of 5 male and 5 female rats per route of dosing
One group is dosed intravenously and the second group is dosed by an extravascular route (e.g., oral, percutaneous). The dosages for the 2 groups need not
be identical
Blood is sampled at frequent intervals (e.g., 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48
hr), and plasma levels of the chemical are assayed. The plasma- concentrationtime data are analyzed to obtain the pharmacokinetic profile, including the area
under the curve (AUC). Comparison of the AUCs after extra-vascular and
intravenous dosing, after correcting for the dosage, provides a measure of
bioavailability. Alternatively, if a radioactive chemical is used, comparison of the
administered doses excreted in urine can be used to calculate the approximate
bioavailability of the orally dosed chemical.
P102-R Optional Studies
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Species other than rats
Plasma protein-binding study
Pharmacokinetics Studies of Nucleotide Therapeutics
We can conduct tissue distribution studies of nucleotide-based materials using
quantitative polymerase chain reaction (PCR), capillary electrophoresis, or in situ
hybridization methods. Studies are designed to fit the needs of each particular test
article.
Comparative Metabolism and In Vitro Toxicity Studies
Incubation with In Vitro Preparations*
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Liver, kidney, small intestine from humans, dogs, monkeys, or rodents
Isolated cells, tissue slices, or subcellular fractions (S9, microsomes, or cytosol,
with cofactors)
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Two test chemical concentrations, 3 time points
Protein assay for standardization
Cytochrome P450 activity and isozyme profile available
Drug-Drug Interaction Studies
V403 Determination of Cytochrome P450 Form-Specific Metabolism · Measure
metabolism of form-specific substrate · Correlation assay with six form-specific activities ·
Confirmation with microsomes from cells expressing single form of human P450
V404 Cytochrome P450 Inhibition · Three drug concentrations · Pooled human liver
microsomes from six donors · Six P450 form-specific assays for CYP1A, 2A6, 2C9, 2C19, 2D6, and
2E1
Cytochrome P450 Induction · Hepatocytes in primary culture · Preliminary range finding
experiment · Definitive experiment with 5 concentrations · Measurement of marker enzyme
activities, confirmed by Western blotting · Available in rat or human hepatocytes
Peroxisome Proliferation Studies
Palmitoyl CoA-Oxidation · Hepatocytes in primary culture · Preliminary cytotoxicity experiment ·
Definitive experiment with 5 concentrations of the test agent and solvent and positive controls ·
Palmitoyl CoA-oxidation as endpoint · Four independent cultures per concentration in each
experiment · Concurrent measurement of DNA or protein levels in each culture
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V301 Rat Hepatocytes
V302 Human Hepatocytes
Cytotoxicity Assays
Cytotoxicity Assays In Primary Cultures
Screening Assays · Hepatocytes or renal proximal tubules · Two experiments with 6
concentrations tested with positive, solvent, and media controls · Four replicate samples, 3 time
points (conducted in 96-well dishes) · FIVE COMPOUNDS MINIMUM.
 V201 Enzyme Release (lactate dehydrogenase)
 V202 MTT Conversion (Mitochondrial Function)
Available Species · Human · Rat · Dog · Rabbit · Mouse · Guinea pig · Hamster · Nonhuman
primates
Specific functional assays · Available for determining chemical mechanism of action and include
urea synthesis, protein synthesis, lipid peroxidation, and oxygen
consumption, among others.
Hemolytic Potential and Compatibility Assays
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C100 Hemolytic Potential in Rat or Dog Blood · Whole rat or dog blood is exposed
to the test article and the amount of hemoglobin released from lysed cells is determined
spectrophotometrically · Untreated controls, vehicle controls, and positive controls are
included · Known volumes of whole blood are used to generate a standard curve
representing 0% to 100% hemolysis
M108-A Hemolytic Potential in Human Blood · Same as C100 but using human
blood
M108-B Hemolytic Potential in Rat, Dog, and Human Blood · Same as M100 but
using blood from all three species
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M108-C Optional Plasma and Serum Compatibility · Concurrent with M108, M108A, M100-B Compatibility is determined by adding the test article to plasma and serum,
individually, and then assessing the occurrence or non-occurrence of precipitation or
coagulation of plasma or serum protein
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