Late Stage Drug Development Flashcards Preview

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Flashcards in Late Stage Drug Development Deck (53):
1

what do you use to test for intestinal absorption>

a Caco-2 cell monolayer

2

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

50%

3

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

20

4

general cytotoxicity studies include

ATP measurement, MTS, enzyme release

5

to check for mitochondrial dysfunction:

look at oxygen consumption

6

hERG potassium channel inhibition can cause

life-threatening arrhythmias

7

drug-drug interactions are usually _________ related

metabolism

8

paracellular and transcellular are forms of ____ uptake

passive

9

carrier mediated uptake is a form of ____ uptakes

active

10

Efflux is mediated by __________

p-glycoprotein

11

Caco-2 cells exhibit __________ mechanisms

all forms of uptake and efflux

12

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

apical

13

the blood side of a membrane is called the __ side

basolateral

14

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

one, a monolayer

15

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

animal/ intact/ harder to grow and use

16

microsomes:

subcellular fraction of digested liver

17

microsomes consist of ________

endoplasmic reticulum

18

microsomes contain ____ enzymes only

phase I

19

____ and ______ are phase I enzymes

CYP450/ FMO

20

microsomes are _____ to use than hepatocytes

easier

21

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

10 minutes/ 20 minutes

22

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

chemicals/ hepatocytes or microsomes/ incubate/ extract/ analyze

23

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

chemicals/ hepatocytes/ P450 substrate/ metabolites

24

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

MTS/ MTT colorimetric assay

25

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

lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase

26

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

90

27

where is the programmed cell death control center located?

in the mitochondria

28

what are three main screens for mitochondrial toxicity?

disrupted energy metabolism, increased free radical generation, altered apoptosis

29

name four screening assays to check for energy metabolism disruption

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

30

name a screening assay that checks for free radical production

ROS production

31

name a screening assay that checks apoptosis induction

PARP activation

32

name three mechanistic assays that check energy metabolism disruption

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

33

name three mechanistic assays used to check for free radical production

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

34

name two mechanistic assays use to check for apoptosis induction

cell fractionation and protein translocation panel, apoptosis protein expression panel

35

normal heart rhythms are governed by

electrical pulses (based on ion transport)

36

disruption of the electrical pulses that regulate heart rhythms results in

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

37

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

out of

38

name two drugs that are hERG inhibitors

fluroquinolones, terfenadine

39

what test can you use to check for genotoxicity?

Ames test

40

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

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

41

acute toxicity studies:

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

42

chronic toxicity studies:

should be for the length of the clinical trial

43

therapeutic index:

LD50/ED50

44

phase I trials provide ___________ and determine _______

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

45

initial dose is usually _____ for phase I trials

1/10 of MELD10

46

______ ______ volunteers are used in a phase I trial

20-100/ healthy

47

________ interactions studies are performed in phase I trials

drug-food

48

how long are drug patents for?

20 years

49

four main criteria for patentability:

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

50

patent claims are written to cover ____

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

51

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

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

52

name four hERG channel inhibitors

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

53

name two types of hERG channel inducers

barbiturates, HIV reverse transcriptase inhibitors