Transcript Drug Action Measurement

Measuring Drug Action
 Dose – Response Curves
R
+
D
KA
KD
R:D
Response
Response  fraction bound (fb) =
Fraction bound
[ R : D]
[ R : D]
K A[ R][ D]
[ D]



[ R]O
[ R]  [ R : D] [ R]  K A[ R][ D] K D  [ D]
1.0
0.5
[D] = KD
0.0
[D]
MEDC 603 Fall 2007
1
Measuring Drug Action
 Dose – Response Curves
D in system
‘R:D’
Response
Response
100 %
90%
50%
IC50 or EC50 or LD50
IC90 or EC90 or LD90
Inhibition Concentration
Effective Concentration
Lethal Dose
0%
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
Response
100 %
~30 %
Drug 2
0%
Log [antagonist]O
MEDC 603 Fall 2007
3
Measuring Drug Action
 Efficacy and Potency
D1
% Response
100
More
potent
than D2
D2
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
100
100
50
50
0
0
Toxicity (%)
Desired Response (%)
 Efficacy / Potency / Toxicity
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
T
S
[A] =0
S
of Enz:
Inhibition
Response
100 %
Color Development
Activity of Enzyme
=
T
S
[A] = max
KI or IC50
0%
Time (s)
Log[anticoagulant]
[antagonist]O
Log
MEDC 603 Fall 2007
6
Measuring Drug Action
 How are these drug-response profiles generated?

Cellular/Pharmacological assays
Cell Viability Assay
100 %
Response
Drug
Mouse Tail Flick Assay
I C50 or EC50 or LD50
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