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Fundamentals of Bio Orgo > Late Stage Drug Development > Flashcards

Late Stage Drug Development Flashcards

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Biology 101 flashcards
1
Q

what do you use to test for intestinal absorption>

A

a Caco-2 cell monolayer

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2
Q

if a drug has stability against CYP450, less than ____ metabolism to the drug will occur after 1 hour

A

50%

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3
Q

for in vivo metabolic stability studies, greater than _______ percent of the drug should remain after 1 hour in rodents

A

20

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4
Q

general cytotoxicity studies include

A

ATP measurement, MTS, enzyme release

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5
Q

to check for mitochondrial dysfunction:

A

look at oxygen consumption

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6
Q

hERG potassium channel inhibition can cause

A

life-threatening arrhythmias

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7
Q

drug-drug interactions are usually _________ related

A

metabolism

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8
Q

paracellular and transcellular are forms of ____ uptake

A

passive

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9
Q

carrier mediated uptake is a form of ____ uptakes

A

active

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10
Q

Efflux is mediated by __________

A

p-glycoprotein

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11
Q

Caco-2 cells exhibit __________ mechanisms

A

all forms of uptake and efflux

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12
Q

the small intestine side of a membrane is called the _______ side

A

apical

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13
Q

the blood side of a membrane is called the __ side

A

basolateral

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14
Q

how many layer of cells are used in Caco-2 testing

A

one, a monolayer

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15
Q

hepatocytes are isolated from ____ and used as _______ cells. They contain the entire range of metabolic enzymes. A downside is that they are ____

A

animal/ intact/ harder to grow and use

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16
Q

microsomes:

A

subcellular fraction of digested liver

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17
Q

microsomes consist of ________

A

endoplasmic reticulum

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18
Q

microsomes contain ____ enzymes only

A

phase I

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19
Q

____ and ______ are phase I enzymes

A

CYP450/ FMO

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20
Q

microsomes are _____ to use than hepatocytes

A

easier

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21
Q

metabolism stability: half life should definitely be over _______, and _____ would probably be good to proceed to the next step

A

10 minutes/ 20 minutes

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22
Q

To do stability tests: start with a 96 well plate. Add ________. Then add ________. Now _________. Then ________ and ______ –> quantification of parent compound disappearance

A

chemicals/ hepatocytes or microsomes/ incubate/ extract/ analyze

23
Q

to see if a drug inhibits CYP450, add ___, then ____ and incubate. Then add ____, incubate, and check for ______.

A

chemicals/ hepatocytes/ P450 substrate/ metabolites

24
Q

toxicity can be measured as hepatocyte viability in the presence of the drug using _____

A

MTS/ MTT colorimetric assay

25
Q

name three cytoplasmic enzymes that can be tested for to analyze the amount of cell death

A

lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase

26
Q

_____ percent of the cell’s energy is produced in the mitochondria

A

90

27
Q

where is the programmed cell death control center located?

A

in the mitochondria

28
Q

what are three main screens for mitochondrial toxicity?

A

disrupted energy metabolism, increased free radical generation, altered apoptosis

29
Q

name four screening assays to check for energy metabolism disruption

A

ATP production (reduction = toxicity), membrane potential, oxygen utilization, mt biogenesis

30
Q

name a screening assay that checks for free radical production

A

ROS production

31
Q

name a screening assay that checks apoptosis induction

A

PARP activation

32
Q

name three mechanistic assays that check energy metabolism disruption

A

OXPHOS Enzyme activity, phospo + acetyl, metabolic protein expression panel

33
Q

name three mechanistic assays used to check for free radical production

A

protein nitration panel, protein oxidation panel, antioxidant protein expression panel

34
Q

name two mechanistic assays use to check for apoptosis induction

A

cell fractionation and protein translocation panel, apoptosis protein expression panel

35
Q

normal heart rhythms are governed by

A

electrical pulses (based on ion transport)

36
Q

disruption of the electrical pulses that regulate heart rhythms results in

A

prolonged QT interval (prolonged heart beat) eventually arrythmias and possibly death

37
Q

the hERG potassium channel is the major protein responsible for conducting K+ ions ____ the heart muscle cells

A

out of

38
Q

name two drugs that are hERG inhibitors

A

fluroquinolones, terfenadine

39
Q

what test can you use to check for genotoxicity?

A

Ames test

40
Q

You need ___________, _____________, ________ and ____ studies to open an IND

A

proof of principle in most appropriate animal model, acute and chronic toxicity studies, safety pharmacology (respiratory, CVS, CNS), ADME panels

41
Q

acute toxicity studies:

A

one large dose or several large does given over less than two weeks

42
Q

chronic toxicity studies:

A

should be for the length of the clinical trial

43
Q

therapeutic index:

A

LD50/ED50

44
Q

phase I trials provide ___________ and determine _______

A

initial pharmacologic and pharmacokinetic data/ maximum tolerable dosage (MTD)

45
Q

initial dose is usually _____ for phase I trials

A

1/10 of MELD10

46
Q

______ ______ volunteers are used in a phase I trial

A

20-100/ healthy

47
Q

________ interactions studies are performed in phase I trials

A

drug-food

48
Q

how long are drug patents for?

A

20 years

49
Q

four main criteria for patentability:

A

novelty, inventive step, enablement, support (justification for claims of efficacy)

50
Q

patent claims are written to cover ____

A

a wide range of compounds in a given class (scaffold)

51
Q

terfenadine is a prodrug _____ converted to ______– by ________. It is a _______.

A

antihistamine/ fexofenadine (Allegra)/ CYP 450 3A4/ hERG channel inhibitor

52
Q

name four hERG channel inhibitors

A

HIV protease inhibitors, Gleevec (cancer drug), ketoconazonle, grapefruit juice

53
Q

name two types of hERG channel inducers

A

barbiturates, HIV reverse transcriptase inhibitors

Fundamentals of Bio Orgo (9 decks)

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