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Drug Discovery and Development > Preclinical Phase : In Vitro Techniques > Flashcards

Preclinical Phase : In Vitro Techniques Flashcards

1
Q

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

A

Lipophilicity

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2
Q

important physicochemical property of a potential drug

A

Lipophilicity

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3
Q

It plays a role in solubility, absorption, membrane penetration, plasma protein binding, distribution, CNS penetration andpartitioning into other tissues or organs such as the liver and has an impact on the routes of clearance.It is important in ligand recognition, not only to the target protein but also CYP450 interactions, HERGbinding, and PXR mediated enzyme induction.

A

Lipophilicity

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4
Q

takes into account the compound’s ionized and non-ionized forms, and therefore the measurement, is done at different pH values

A

distribution coefficient, log D

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5
Q

typically measured as the neutral (non-ionized) compound distribution betweennon-aqueous (octanol) and aqueous (water) phase and the result is expressed as a 10-base logarithmof the concentration ratios between these phases (partition coefficient), log P

A

Lipophilicity

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6
Q

Test articles are assayed in triplicate

A

Lipophilicity, Hepatic Microsome Stability, Plasma Stability, Permeability

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7
Q

partition solvent of lipophilicity

A

n-octanol

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8
Q

positive control of lipophilicity

A

testosterone

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9
Q

negative control of lipophilicity

A

tolbutamide

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10
Q

lipophilicity of compounds is assessed using the golden standard

A

shake-flask method

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11
Q

“What is the bioavailability of my compound?”

A

Solubility

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12
Q

an important analysis as it reflects the bioavailability of the compound

A

Aqueous solubility

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13
Q

majority of known drugs contain ionizable groups

t or f

A

t

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14
Q

test articles are assayed in duplicate

A

Solubility, plasma protein binding

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15
Q

positive control for solubility

A

Diclofenac

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16
Q

example of high solubility

A

Diclofenac

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17
Q

negative control for solubility

A

Dipyridamole

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18
Q

example of low solubility

A

Dypyridamole

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19
Q

The compound is allowed to reach thermodynamic equilibrium by incubating for 18 hours
t or f

A

True

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20
Q

Pharmacologic question addressed: “How long will my parent compound remain circulating in plasma within the body?”

A

Hepatic Microsome Stability

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21
Q

consist mainly of endoplasmatic reticulum and contain many drug-metabolizing enzymes, including cytochrome P450s (CYPs), flavin monooxygenases, carboxylesterases, and epoxide hydrolase

A

Liver Microsomes

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22
Q

The assay uses subcellular fractions of liver microsomes, to investigate the metabolic fate of compounds.

A

Hepatic Microsome Stability

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23
Q

available commercially (example, Xenotech, LifeTechnologies and DB Biosciences) as frozen preparations that are usually prepared in bulk with pooled livers from sacrificed mice, rat or human cadavers

A

Liver Microsomes

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24
Q

positive control for hepatic microsome stability

A

Substrates with known activity

25
Q

negative control for hepatic liver microsome

A

NADPH deficient

26
Q

Pharmacologic question addressed: “Is my compound degraded in plasma?”

A

Plasma Stability

27
Q

What enzyme in plasma are compounds subjected to degradation or modification

A

hydrolysis and esterases

28
Q

an important parameter, which not only affects in vivo results, but also the bioanalytical assay strategy and design.

A

stability of test compounds in plasma

29
Q

positive control for plasma stability

A

Procaine

30
Q

negative control for plasma stability

A

Procainamide

31
Q

Pharmacologic question addressed: “What percent of the compound plasma protein is bound, to which component (sub-fraction), and what is the free fraction available to cover the target?”

A

Plasma Protein Binding

32
Q

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

A

Rapid Equilibrium Dialysis

33
Q

Blank, isotonic sodium phosphate buffer is added to the peripheral chamber of the RED device and the plate is incubated at

A

37degree celsius for 4 hours

34
Q

Pharmacologic question addressed: “Is my compound too toxic to be therapeutic?”

A

Screening Cytotoxicity

35
Q

a well-established and easily accessible endpoint to gather early information about the general / acute toxic potential of a test article

A

Cytotoxicity

36
Q

a single reagent addition, homogeneous, luminescence ATP detection assay that measures the number of live cells in culture wells

A

ATP-lite 1step Cytotoxicity Assay

37
Q

are incubated for 24 hours with known toxic and non-toxic compounds at a range of different concentrations

A

hepatocyte cells

38
Q

This assay extends the findings of the microsomal stability assay.

A

CYP450 Inhibition Profiling

39
Q

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

A

CYP450 Inhibition Profiling

40
Q

superfamily of heme-containing enzymes that mediate the inactivation and metabolism of many drugs as well as endogenous substances

A

Cytochrome P450s

41
Q

Compounds that inhibit P450s cannot cause the toxic accumulation of other substrates.

A

False, it can cause

42
Q

five primary drug human metabolizing CYP

A

1A2, 2B6, 2C9, 2D6, 3A4

43
Q

Pharmacologic question addressed: “How well is my drug absorbed in the gastrointestinal tract?”

A

Permeability

43
Q

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

A

Liver Microsome

44
Q

a good indication of intestinal permeability and oral bioavailability.

A

Evaluating compound permeability through a cell monolayer

45
Q

provides a high throughput, non-cell based method for predicting passive, transcellular intestinal absorption, the process by which the majority of small molecule drugs enter circulation.

A

Parallel Artificial Membrane Permeability Assay (PAMPA)

46
Q

an artificial membrane immobilized on a filter is placed between a donor and acceptor compartment

A

PAMPA method

47
Q

PAMPA

A

Parallel Artificial Membrane Permeability Assay

48
Q

a pH range from pH 1 – 8

A

gastrointestinal tract

49
Q

constant pH of the blood

A

7.4

50
Q

a well-established and predictive assay that models the absorption of drugs in the gut.

A

PAMPA

51
Q

useful tool to prioritize lead compounds in early stages of development

A

PAMPA

52
Q

Industry standard for in vitro prediction of intestinal absorption of drugs, but it too has limitations

A

colon carcinoma (Caco-2) cell permeability assay

53
Q

one variant of PAMPA

A

blood

53
Q

Require extensive culturing (>20 days), and often fail to form the cohesive monolayer necessary for uniform transport of compounds across the cell layer.

A

Caco-2 cells

54
Q

where the artificial monolayer contains brain specific membrane components, such as sphingolipids.

A

Brain Barrier (BBB) PAMPA

55
Q

Quantity of test article required for permeability

A

5.0 - 7.0 mg

55
Q

established on a membrane filter and a test compound solution is added to the top of the membrane-lipid interface.

A

lipid bilayer

Drug Discovery and Development (1 decks)

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