Structural Properties 5 Lecture

Question 1

Define drug metabolism

Answer 1

The chemical alteration of a drug by a biological system with principal purpose of eliminating it from the system
Usually involves increasing solubility

Question 2

Define pharmacokinetics

Answer 2

Study of the movement of drugs within the body

What the body does to the drug?

Question 3

Define pharmacodynamics

Answer 3

Study of the pharmacological response to a drug

What the drug does to the body

Question 4

DMPK

Answer 4

Drug Metabolism and Pharmacokinetics

Question 5

Why study DMPK?

Answer 5

Compare drug candidates: need to understand how they behave in the body in order to have confidence that they will be safe and efficaceous

Question 6

Define ADMET

Answer 6

Absorption
Distribution
Metabolism
Excretion
Temperature

Question 7

Define absorption

Answer 7

process by which a drug moves from its site of admin to the systemic circulation

Question 8

Define distribution

Answer 8

Reversible transfer of a drug to and from the systemic circulation

Question 9

Define metabolism

Answer 9

Any chemical alteration of a drug by the living system to enhance water solubility and hence excretion

Question 10

Define excretion

Answer 10

The irreversible transfer of a drug from the systemic circulation

Question 11

Factors that affect absorption are?

Answer 11

Solubility
Acid Stability
Permeability
Metabolism

Question 12

Define metabolism

Answer 12

Any chemical alteration of a drug by the living system

- Enhances water solubility and excretability

Question 13

Define Phase 1 metabolism

Answer 13

Production of a new chemical group on the molecule (grps that enhance or increase solubility)

Question 14

Define Phase 2 metabolism

Answer 14

Addition of an endogenous ligand to the molecule

Question 15

Where is the site of metabolism

Answer 15

Liver mainly

+ GI wall, kidney, blood

Question 16

What affects metabolism?

Answer 16

Structure of the drug
MW, LogP/D, pKa
More complex the structure the more potential sites for metabolism

Question 17

What is oxidation in phase 1?

Answer 17

Add water soluble groups to CH bonds

- Add OH to increase solubility

Question 18

What is reduction in phase 1?

Answer 18

O –> OH

Increase H bonding

Question 19

What is hydrolysis in phase 1?

Answer 19

Take an ester, chop it off

More water soluble

Question 20

What can happen in phase 2?

Answer 20

Glucuronidation: adding a sugar molecule
Amino acid addition
Acetylation: adding an acetyl group to an amine group
Sulfation: adding a sulfur group
Glutathione conjugation: electrophile

Question 21

Why do most drug candidates fail?

Answer 21

1 in 9

First bad at PK now toxicology

Question 22

CYP-450 mediate?

Answer 22

Many Phase I oxidations
Membrane bound proteins (on the ER)
Heme containing proteins

Question 23

Pre-clinical toxicology is used for?

Answer 23

Demonstrate safety in vitro and in vivo

Question 24

Pre-clinical toxicology assumptions?

Answer 24

In vitro predict in vivo effects
Effects of chemicals in lab animals apply to human
Use of high doses in animals is valid for predicting possible toxicity in humans

Question 25

Toxic effect include?

Answer 25

Mechanism based pharmacology
Formation of reactive metabolites
Activation of other receptors, including hERG
Interactions with other substances
Idiosyncratic toxicity (not sure why toxic)

Question 26

What is mechanism based pharmacology?

Answer 26

Actual toxic effect comes from inhibiting or doing whatever the drug is doing; inhibiting the enzyme
May have toxic effects later on down the road

Question 27

What is COX-2 inhibitors good at?

Answer 27

Reducing inflammation and anticancer activitty

Can result in cardiovascular toxicity

Question 28

Define beta-agonists

Answer 28

Used to control asthma by causing activation of the beta-2 receptors in the lung

• Causes the airways to dilate
• Take compounds are taken by inhalation, so drugs stay in lungs

Question 29

Formation of reactive metabolites

Answer 29

Don’t want chemically reactive medicines

Avoid aldehydes

Question 30

Define electrophiles

Answer 30

They can covalently bind to nucleophiles in the body (can lead to toxic effects)

Question 31

How can you avoid toxic effects?

Answer 31

Avoid functional groups known to show reactive metabolites (nitro groups, nitroaryls)
Test for presence of such groups
Ames testing for mutagenicity

Question 32

What is activation of other receptors/enzymes?

Answer 32

“off target toxicity”
Screen against other systems
Potency is important in safety as well

Question 33

What is the hERG test

Answer 33

hERG: human ether-a-go-go related gene
Potassium ion channel in cardiac cell membranes
Activation causes prolongation of electrical impulses regulating heart beat –> fatal arrhythmias

Question 34

Importance of hERG?

Answer 34

A wide variety of drugs bind to it that have different structures; avoid the structure and lower toxicity