DDD (SAS 6-7)

Lipophilicity

Lipophilicity

plays a role in solubility, absorption, membrane penetration, plasma protein binding, CNS penetration, and more.

log P (partition coefficient)

expressed as a 10-base logarithm of the concentration ratios between these phases

log D (distribution coefficient)

measure lipophilicity which takes into account the compound’s ionized and non-

n-Octanol

the partition solvent of lipophilicity assay

testosterone

positive control of lipophilicity assay

tolbutamide

the negative control in lipophilicity assay

shake-flask method

lipophilicity of compounds are assessed using this golden standard

Aqueous solubility

this analysis reflects the bioavailability of the compound

Diclofenac

the positive control used in solubility

Dipyridamole

the negative control used in solubility assay

DMSO

the background control used in solubility assay

UV spectrophotometry

the instrument used to measure the parent compound of the solubility assay

liver microsomes

consist mainly of endoplasmic reticulum and contain many drug-metabolizing enzymes; frozen preparations

substrates with known activity

the positive control used in hepatic microsome stability

NADPH deficient

the negative control used in hepatic microsome stability assay

Procaine

the positive control used in plasma stability assay

procainamide

the negative control used in plasma stability assay

aliquots

are removed at predefined time points and analyzed by LC/MS/MS

drug efficacy

determined by the concentration of free drug

Rapid Equilibrium Dialysis (RED)

an accurate and reliable method for determining the degree to which a compound binds to plasma proteins

Propranolol

the high binding positive control of plasma protein binding assay

Metoprolol

the low binding positive control of plasma protein binding assay

no plasma (PBS only)

the negative control of plasma protein binding assay

ATP-lite 1step Cytotoxicity Assay

measures the number of live cells in culture wells

CYP inhibition profiling

examines the effects of a test compound on the metabolism of other known enzyme substrates

CYP marker reaction

the positive control in CYP450 Inhibition Profiling assay

NADPH deficient reaction

the negative control in CYP450 Inhibition Profiling Assay

Parallel Artificial Membrane Permeability Assay (PAMPA)

provides a high throughput, non-cell based method for predicting passive, transcellular intestinal absorption; mimics absorption of the gut

liver microsomes

used to determine the CYP450 inhibition profile of test compounds measuring the % metabolism of a known substrate

Permeability

answers “How well is my drug absorbed in the GI tract?”

pH 1-8

pH range of the GI tract

pH 7.4

the pH of the blood

Colon Carcinoma (CaCo-2) cell permeability assay

the industry standard for in vitro prediction of intestinal absorption of drugs

sphingolipids

the brain specific membrane component

compounds with known toxicity

the positive control used in the Screening Cytotoxicity/ Hepatotoxicity test

compounds with known non-toxicity

the negative control used in the Screening Cytotoxicity/ Hepatotoxicity test

Luminescence

the analysis used in the Screening Cytotoxicity/ Hepatotoxicity Test

Verapamil

the positive control used in the Permeability assay

Theophylline

the negative control used in the Permeability Assay

UV spectrophotometry

the instrument used in the analysis of Permeability assay

5.0-7.0 mg

the quantity of test article required in the Permeability assay

Lipophilicity

answers “Will my parent compound be stored in lipid compartments or how well will my parent compound bind to a target protein?”

Solubility

answers “What is the bioavailability of my compound?”

Hepatic Microsome Stability

answers “How long will my parent compound remain circulating in plasma within the body?”

Plasma Stability

answers “Is my compound degraded in plasma?”

Plasma Protein Binding

answers “What percent of the compound plasma protein is bound, to which component, and what is the free fraction available to cover the target?”

Screening Cytotoxicity/ Hepatotoxicity Test

answers “Is my compound too toxic to be therapeutic?”

24 hours

How many hours are hepatocyte cells incubated in the Screening Cytotoxicity/ Hepatotoxicity Test?

18 hours

How many hours does the compound used in Solubility test incubated to reach thermodynamic equilibrium?

CYP450 Inhibition Profiling

answers “Does my compound inhibit a key oxidative metabolic enzyme that would lead to a subsequent drug-drug interactions?”

Laboratory animals

any vertebrae animal produced for or used in research, testing, or teaching

Animal use

the proper care, use, and humane treatment of laboratory animals produced for or used in research, testing, or teaching

Three Rs

an internationally accepted approach for researchers to apply when deciding to use animals in research and in designing humane animal research studies

Replacement

refers to methods that avoid using animals

Absolute Replacement

replacing animals with inanimate systems such as computer programs

Relative Replacement

replacing animals such as vertebrates with animals that are lower on the phylogenetic scale

Refinement

refers to modifications of husbandry or experimental procedures to enhance animal well-being and minimize or eliminate pain and distress

Reduction

involves strategies for obtaining comparable levels of information from the use of fewer animals or for maximizing the information obtained from a given number of animals

True animal model

one in which the disease in the animal is reproducible and more importantly, predictable

Experimental model

one in which the experimentally reproduced condition mimics a human disease

ex. Leprosy in Armadillos

Negative model

also called ‘non-model’ which refers to an animal species in which a particular disease cannot be produced

Negative model

used to study why this animal is resistant to a particular disease

ex. Wood rat- immune to snake bite

ex. Opossum- resistant to rabies

Spontaneous model

an animal species that has a disease which occurs naturally and mimics a human disease at least in some way

ex. Stumptailed macaques- baldness

ex. VonWillebrands Disease- Factor A Hemophilia

Orphan model

an animal disease that does not mimic a human disease and may not be recognized as a true model

Republic Act No. 8485

also known as the Animal Welfare Act of 1998

Euthanasia

the process of inducing painless death to pets

Guideline 1

SCIENTIFIC AND SOCIAL VALUES AND RESPECT FOR RIGHTS

Guideline 1

in order to be ethically permissible, health-related research with humans must have social value

seeding trials

the purpose is to influence clinicians who participate in the study to prescribe a new medication rather than to produce knowledge

Social Value

refers to the importance of the information that a study is likely to produce

Scientific value

refers to the ability of a study to produce reliable, valid information capable of realizing the stated objectives of the research

Guideline 2

RESEARCH CONDUCTED IN LOW-RESOURCE SETTINGS

Guideline 2

pertains to settings in which resources are so limited that the population may be vulnerable to exploitation by sponsors and investigators from wealthier countries and communities

Guideline 3

EQUITABLE DISTRIBUTION OF BENEFITS AND BURDENS IN THE SELECTION OF INDIVIDUALS AND GROUPS OF PARTICIPANTS IN RESEARCH

Guideline 3

it requires that the benefits of research be distributed fairly and that no group or class of persons bears more than its fair share of the risks or burdens from research participation

Guideline 4

POTENTIAL INDIVIDUAL BENEFITS AND RISKS OF RESEARCH

Guideline 4

researchers must first assess the risks and potential individual benefits of each individual research intervention and procedure, and then judge the aggregate risks and potential individual benefits of the study as a whole

Data Safety and Monitoring Committee (DSMC)

reviews and decide data on harms and benefits as a study progresses

minimal-risk standard

defined by comparing the probability and magnitude of anticipated harms with the probability and magnitude of harms ordinarily encountered in daily life

Guideline 5

CHOICE OF CONTROL IN CLINICAL TRIALS

Guideline 5

methodologically essential in order to test the relative merits of investigational interventions

Randomization

the preferred method for assigning participants to the arms of controlled trials

Guideline 6

CARING FOR PARTICIPANT’S HEALTH NEEDS

Guideline 6

research with humans often involves interactions that enable researchers to detect or diagnose health problems during recruitment and the conduct of research

Guideline 6

clinical research often involves care and preventive measures in addition to the experimental interventions

Guideline 7

COMMUNITY ENGAGEMENT

Guideline 7

proactive and sustained engagement with the communities from which participants will be invited to participate is a way of showing respect for them and the traditions and norms they share

community engagement

a means of ensuring the relevance of proposed research to the affected community, as well as its acceptance by the community

Guideline 8

COLLABORATIVE PARTNERSHIP AND CAPACITY-BUILDING FOR RESEARCH AND RESEARCH REVIEW

Guideline 8

ensure that such research is reviewed ethically and scientifically by competent and independent research ethics committees and is conducted by competent research teams

Guideline 9

INDIVIDUALS CAPABLE OF GIVING INFORMED CONSENT

Guideline 9

researchers have a duty to provide potential research participants with the information and the opportunity to give their free and informed consent to participate in research

Guideline 10

MODIFICATIONS AND WAIVERS OF INFORMED CONSENT

Guideline 10

researchers should first seek to establish whether informed consent could be modified in a way that would preserve the participant’s ability to understand the general nature of the investigation and to decide whether to partipate

Guideline 11

COLLECTION, STORAGE, AND USE OF BIOLOGICAL MATERIALS AND RELATED DATA

Guideline 11

when biological materials and related data, such as health or employment records, are collected and stored, institutions must have a governance system to obtain authorization for future use of these materials in research

Guideline 13

REIMBURSEMENT AND COMPENSATION FOR RESEARCH PARTICIPANTS

Guideline 13

Research participants should be reasonably reimbursed for costs directly incurred during the research

Guideline 14

TREATMENT AND COMPENSATION FOR RESEARCH-RELATED HARMS

Guideline 14

sponsors and researchers must ensure that research participants who suffer physical, psychological, or social harm as a result of participating in health-related research receive free treatment rehabilitation for such harms