Basic Pharmacology
Lecture 9
Drug Discovery and Biotechnology
Why do drugs Fail?
Activity or Drug Properties
Activity
Pharmacology
Drug-like Properties
The Challenge & Goal of Drug
Discovery
Good
Drugs
Activity Optimization
Activity
Good
D-lead
Kerns & Di (2008) Drug-like Properties:
Concepts, Structure, Design, & Methods
Pharmacology
Studying the interaction between the drug and body
Drug-lead
Pharmacokinetics
ADME
Pharmacodynamics
MOA, Toxicity, etc
Drug-like properties
ü
ü
ü
ü
ü
Will be absorbed from GIT
Will have enough concentration/time at the target
Will cross the BBB, placenta, offspring
What is the dose?
Any predicted side effects?
Thalidomide catastrophe
Therapeutic index (TI)
LD50/ED50
The higher the TI, the safer the drug
Remifentanil 33,000:1
Diazepam 100:1
Cocaine 15:1
Digoxin 2:1
Fate of Drug after Administration
•
•
•
•
Absorption
Distribution
Metabolism
Excretion
A
D
M
E
Concentration-time curve
Dose
Blood samples
logP: Partition co-efficient
Ratio of concentration of a compound in oil phase
“octanol” and water phase
LogP= log10 [in octanol]/[in water]
Meaning of logP
Positive value
LogP
Zero
lipophilic
Equal
Negative value
hydrophilic
High LogP
Ø
Ø
Ø
Ø
Ø
More absorption
Cross body barrier
Distribution more to tissue
Binding to target, more efficacy
Binding to other targets and be retained,
more toxicity
LogP fro drugs launched/published
from 1965 to 2005
Pharmacokinetics (PK)
•
•
•
•
Absorption
Distribution
Metabolism
Excretion
A
D
M
E
Absorption
ØPassive diffusion
ØActive transport
ØPinocytosis
PAMPA assay
Parallel Artificial Membrane Permeability Assay
PAMPA Assay
hexadecane
The concentration of the test agent is measured on the donor and acceptor
compartments using either HPLC, LC/MS/MS, or UV spectroscopy.