Structural Properties 5 Lecture Flashcards by Beth Cocker

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

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Define pharmacokinetics

Study of the movement of drugs within the body

What the body does to the drug?

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Define pharmacodynamics

Study of the pharmacological response to a drug

What the drug does to the body

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DMPK

Drug Metabolism and Pharmacokinetics

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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

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Define ADMET

Absorption
Distribution
Metabolism
Excretion
Temperature

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Define absorption

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

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Define distribution

Reversible transfer of a drug to and from the systemic circulation

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Define metabolism

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

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Define excretion

The irreversible transfer of a drug from the systemic circulation

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Factors that affect absorption are?

Solubility
Acid Stability
Permeability
Metabolism

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Define metabolism

Any chemical alteration of a drug by the living system

- Enhances water solubility and excretability

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Define Phase 1 metabolism

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

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Define Phase 2 metabolism

Addition of an endogenous ligand to the molecule

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Where is the site of metabolism

Liver mainly

+ GI wall, kidney, blood

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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