3 Kruse DSA's - 8/3 Kruse

Question 1

What is the chemical modification of lipophilic, unionized, or large compounds to terminate their actions and facilitate elimination called?

Answer 1

Biotransformation

Question 2

What is an example of Biotransformation activation?

Active -> active compound?

Inactivation?

Answer 2

L-dopa -> dopamine

Diazepam -> oxazepam

Aspirin -> acetic acid + salicylate

Question 3

Major site of Biotransformation?

Additional sites?

Answer 3

Liver

Gi tract, lungs, skin, kidneys

Question 4

What is described by the process by which oral drugs are absorbed in the small intestine and transported into the liver via the hepatic portal system, undergoing extensive metabolism?

Answer 4

1st-pass effect

Question 5

Phase I reactions include what kinds of reactions?

Answer 5

PCONS oxidation
Reduction hydrolysis

Less commonly: hydroxylation, epoxidation, dealkylation, deamination, desulfuration, dechlorination

Question 6

What carries out Phase 1 reactions?

Answer 6

CYP
FMO
mEH, sEH

Question 7

Where are phase I enzymes located?

Phase 2?

Answer 7

Lipophilic ER membranes of liver

Liver

Question 8

What is the most important CYP subtype?

What do all CYPs contain?

Answer 8

CYP3A4

Molecule of heme that is noncovalently bound to the polypeptide chain

Question 9

What do P450s need to carry out oxidation of substrates?

Answer 9

NADPH (O2 and H+)

Question 10

Name the most common enzyme inducers

Answer 10

Phenytoin 
Ethanol
Benzo[a]pyrene
Rifampin
Phenobarbital
ST John's wort

Question 11

What effect does grapefruit juice have on drugs taken orally?

Answer 11

Irreversibly inhibit intestinal CYP3A4

Question 12

What effect does allopurinol have on mercaptopurine?

Answer 12

Prolongs the action of mercaptopurine and enhances its chemotherapeutic and toxic effects by inhibiting xanthine oxidase

Question 13

What predisposes neonates to drug toxicity?

Answer 13

Poorly developed BB barrier
Weak Biotransforming activity
Immature excretion mechanisms

Question 14

Toxic doses of acetaminophen can lead to what?

Why?

Answer 14

Hepatotoxicity

GSH is depleted to quickly

Question 15

What are the most common enzyme inhibitors?

Answer 15

Amiodarone
Cimetidine
Grapefruit juice
Azole anti fungal 
Ritonavir (HIV protease inhibitor)

Question 16

What are the P-GP inhibitors?

Answer 16

Verapamil
Mibefradil
Grapefruit juice

Question 17

What drugs are expelled by P-gp and more toxic when given with a P-gp inhibitor?

Answer 17

Digoxin
Cyclosporine
Saquinavir

Question 18

1st pass metabolism of what is greater in men than women?

Answer 18

Ethanol

Question 19

Polymorphisms in what enzyme result in increased toxicity and require reduced dosage which causes diarrhea and neutropenia due to decreased clearance of 5-FU?

Answer 19

DPD

Question 20

CYP2C19 polymorphisms can affect what drugs?

Answer 20

Clopidogrel
Propanolol
Omeprazole
Diazepam
Tricyclics

Question 21

Reduced efficacy (LOF) of clopidogrel results in what?

Answer 21

INC risk of clotting in Pts with CAD

Question 22

What polymorphism is associated with GOF and increased effect and toxicity of codeine?

Answer 22

CYP2D6

Question 23

What is associated with reduced Warfarin clearance?

Answer 23

CYP2C9 with reduced function allele of VCORC1

Question 24

Reduced function of OATPs like SLCO1B1 result in what?

Answer 24

Increased risk of simvastatin myopathy and increased risk of skeletal muscle myopathy

Question 25

What polymorphism is associated with risk of hemolysis and increased resistance to malaria?

Answer 25

G6PD

Question 26

A polymorphism of UGT1A1 results in what?

Answer 26

Decreased clearance and increased toxicity of SN-38

Question 27

What is associated with decreased clearance of 6-mercaptopurine and increased toxicity?

Answer 27

TPMT*2

Question 28

What can increase the metabolism of codeine? What is the active metabolite? Can result in what?

Answer 28

CYP2D6 Morphine Respiratory depression (cyanosis)

Question 29

What kind of design consists of patients receiving each therapy in sequence so that the patients serve as their own controls?

Answer 29

Crossover design

Question 30

What characterizes phase 0 testing in humans?

Answer 30

Micro dosing

Question 31

What phase drug testing examines absorption, half-life, and metabolism?

Answer 31

Phase I

Question 32

How many volunteers is typical of phase I testing?

Answer 32

25-50

Question 33

How many volunteers are used in phase II testing? Primarily looking for what?

Answer 33

100-200 Efficacy, dosing requirements, toxicities

Question 34

How large of a group is used in phase III testing? What techniques are used?

Answer 34

300-3000 Crossover, double-blind

Question 35

When does phase IV testing occur?

Answer 35

After approval to market

Question 36

What does the dominant lethal test assess?

Answer 36

In vivo mutagenicity (loss of embryos or deformed fetus)

Question 37

What test is used for mutagenicity in bacteria?

Answer 37

Ames test

Question 38

Give the order in which they occur of the following: NDA IND Clinical trials

Answer 38

1. IND 2. clinical trial 3. NDA

Question 39

When are the results of chronic toxicity studies in animals required? When do they usually begin?

Answer 39

NDA At the time of the IND submission

Question 40

What SNP is associated with codeine?

Answer 40

CYP2D6

Question 41

What is associated with CYP2C19?

Answer 41

Clopidogrel

Question 42

N-acetyltransferase SNP is associated with what drug?

Answer 42

Isoniazid

Question 43

TPMT SNPs are associated with drugs?

Answer 43

6-mercaptopurine

Question 44

Butyrylcholinesterase SNPs are associated with drug?

Answer 44

Succinylcholine