Structural Properties 5 Lecture Flashcards
Define drug metabolism
The chemical alteration of a drug by a biological system with principal purpose of eliminating it from the system
Usually involves increasing solubility
Define pharmacokinetics
Study of the movement of drugs within the body
What the body does to the drug?
Define pharmacodynamics
Study of the pharmacological response to a drug
What the drug does to the body
DMPK
Drug Metabolism and Pharmacokinetics
Why study DMPK?
Compare drug candidates: need to understand how they behave in the body in order to have confidence that they will be safe and efficaceous
Define ADMET
Absorption Distribution Metabolism Excretion Temperature
Define absorption
process by which a drug moves from its site of admin to the systemic circulation
Define distribution
Reversible transfer of a drug to and from the systemic circulation
Define metabolism
Any chemical alteration of a drug by the living system to enhance water solubility and hence excretion
Define excretion
The irreversible transfer of a drug from the systemic circulation
Factors that affect absorption are?
Solubility
Acid Stability
Permeability
Metabolism
Define metabolism
Any chemical alteration of a drug by the living system
- Enhances water solubility and excretability
Define Phase 1 metabolism
Production of a new chemical group on the molecule (grps that enhance or increase solubility)
Define Phase 2 metabolism
Addition of an endogenous ligand to the molecule
Where is the site of metabolism
Liver mainly
+ GI wall, kidney, blood
What affects metabolism?
Structure of the drug
MW, LogP/D, pKa
More complex the structure the more potential sites for metabolism
What is oxidation in phase 1?
Add water soluble groups to CH bonds
- Add OH to increase solubility
What is reduction in phase 1?
O –> OH
Increase H bonding
What is hydrolysis in phase 1?
Take an ester, chop it off
More water soluble
What can happen in phase 2?
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
Why do most drug candidates fail?
1 in 9
First bad at PK now toxicology
CYP-450 mediate?
Many Phase I oxidations
Membrane bound proteins (on the ER)
Heme containing proteins
Pre-clinical toxicology is used for?
Demonstrate safety in vitro and in vivo
Pre-clinical toxicology assumptions?
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
Toxic effect include?
Mechanism based pharmacology
Formation of reactive metabolites
Activation of other receptors, including hERG
Interactions with other substances
Idiosyncratic toxicity (not sure why toxic)
What is mechanism based pharmacology?
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
What is COX-2 inhibitors good at?
Reducing inflammation and anticancer activitty
Can result in cardiovascular toxicity
Define beta-agonists
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
Formation of reactive metabolites
Don’t want chemically reactive medicines
Avoid aldehydes
Define electrophiles
They can covalently bind to nucleophiles in the body (can lead to toxic effects)
How can you avoid toxic effects?
Avoid functional groups known to show reactive metabolites (nitro groups, nitroaryls)
Test for presence of such groups
Ames testing for mutagenicity
What is activation of other receptors/enzymes?
“off target toxicity”
Screen against other systems
Potency is important in safety as well
What is the hERG test
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
Importance of hERG?
A wide variety of drugs bind to it that have different structures; avoid the structure and lower toxicity
