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For empty boxes in vivo section FOR ADME Pages 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 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: Metabolite isolation and characterization Bioavailability evaluations Bioequivalence studies Formulation screening and optimization Dosing frequency Formulation, Routes of administration, Exposure, Interspecies comparisons. D:\582730125.doc Page 1 of 5 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: 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. 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 D:\582730125.doc Page 2 of 5 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. 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 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* Liver, kidney, small intestine from humans, dogs, monkeys, or rodents Isolated cells, tissue slices, or subcellular fractions (S9, microsomes, or cytosol, with cofactors) D:\582730125.doc Page 3 of 5 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 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 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 D:\582730125.doc Page 4 of 5 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 D:\582730125.doc Page 5 of 5