Measuring Drug Action
Dose – Response Curves
KA
R + D R:D Response
KD
Response fraction bound (fb) =
[ R : D] [ R : D] K A[ R][ D] [ D]
[ R]O [ R] [ R : D] [ R] K A[ R][ D] K D [ D]
1.0
Fraction bound
0.5
[D] = KD
0.0
[D]
MEDC 603 Fall 2007 1
Measuring Drug Action
Dose – Response Curves
D in system ‘R:D’ Response
100 %
90%
Response
IC50 or EC50 or LD50
50%
IC90 or EC90 or LD90
Inhibition Concentration
Effective Concentration
0% Lethal Dose
Log [antagonist]O
Or Log [agonist]O
Agonist: An agent that facilitates or enhances the normal action of a receptor.
Antagonist: An agent that prevents the normal action of a receptor.
MEDC 603 Fall 2007 2
Measuring Drug Action
Dose – Response Curves
Drug 1
100 %
Response ~30 % Drug 2
0%
Log [antagonist]O
MEDC 603 Fall 2007 3
Measuring Drug Action
Efficacy and Potency
More
potent
than D2
D1 D2
100
% Response
D3
Less
efficacious
than D2
0
Log [Drug]
…… Potency corresponds to the strength of a drug, while Efficacy corresponds to the
effectiveness of a drug.
…… e.g., if 1 mg of drug A relieves pain as effectively as 10 mg of drug B, drug A is
twice as potent as drug B
…… the diuretic furosemide eliminates much more salt and water through urine than
does the diuretic chlorothiazide. Thus, furosemide has greater efficacy than
chlorothiazide.
MEDC 603 Fall 2007 4
Measuring Drug Action
Efficacy / Potency / Toxicity
Desired Response (%)
100 100
Toxicity (%)
50 50
0 0
Log [Drug]
Blue lines …. Drug 1
Red lines …. Drug 2
Solid lines …. Desired response
Dotted lines …. Toxicity response
MEDC 603 Fall 2007 5
Measuring Drug Action
How are these drug-response profiles generated?
e.g., anticoagulants and inhibition of pro-coagulant enzymes
Anticoagulant
S S
T S T S
[A] =0 100 %
=
Inhibition of Enz:
Color Development
Response
Activity of Enzyme
KI or IC50
[A] = max
0%
Time (s) Log [antagonist]
Log [anticoagulant] O
MEDC 603 Fall 2007 6
Measuring Drug Action
How are these drug-response profiles generated?
Cellular/Pharmacological assays
Cell Viability Assay
100 %
Drug
Response
I C50 or EC50 or LD50
Mouse Tail Flick Assay
Heat!
0%
Drug Log [antagonist]O
Heat!
MEDC 603 Fall 2007 7
Measuring Drug Action
How are these drug-response profiles generated?
High Throughput Screening Assays
Simultaneous …. 96- or 384-well microtiter plates …. robotic analysis
Chromogenic substrates …. develop color
Yes or No answer ….. fixed concentration of drug
Quantitative …. may also give you KI values!!
96-well microtiter plate
MEDC 603 Fall 2007 8