Download CL (hepatic) vs. Vd

DavidsonX – D001x – Medicinal Chemistry
Chapter 7 – Pharmacokinetics
Part 8 – CL and Vd Revisited
Video Clip – CL vs. Vd Plots
In this chapter on pharmacokinetics, we have covered a number of topics and equations.
While we have been faithful to the topic of pharmacokinetics, we have perhaps lost sight of
medicinal chemistry. We need to bring the discussion back to the relationship between the
molecular structure of a drug and its properties (pharmacokinetics).
Half-life (t1/2) and the elimination rate constant (kel) are determined by clearance (CL) and
volume of distribution (Vd).
If a drug is only cleared by the liver (i.e., renal clearance is zero), then an interesting
relationship between CL and Vd can be established. The slope of such a line is 0.693 / t1/2.
Remember that blood flow to the liver is at most approximately 25 mL/min/kg, and hepatic
clearance is related to oral bioavailability (F).
A plot of CLH vs. Vd is shown below. Each half-life corresponds to a different slope on the
graph. The point of this graph is not that we can generate it. The point is that we can plot a
molecule, based on its CLH and Vd, on this graph and make reasonable decisions on how to
change the structure in order to change its half-life.
CL (hepatic) vs. Vd
hepatic CL (mL/min/kg)
25
t1/2 = 4 h
t1/2 = 8 h
t1/2 = 16 h
20
F = 0.20
15
F = 0.40
10
F = 0.60
5
F = 0.80
0
0
5
10
15
20
25
30
35
Vd (L/kg)
The target half-life for an oral drug is often around 8 hours. This tends to give a drug that can
be dosed once per day. If a lead compound is in development and shows a CLH of 5
mL/min/kg and a Vd of 7 L/kg, then the compound will fall along the 16 h half-life line. This
value is rather high, and the drug discovery group may seek to decrease the half-life.
Decreasing the lead's half-life can be accomplished in a combination of two ways. One, the
Vd of the lead might be decreased to 4 L/kg. A CLH of 5 mL/min/kg and a Vd of 4 L/kg falls on
the 8 h half-life line. Two, the CLH of the lead might be increased to 10 or 11 mL/min/kg. A
CLH of 11 mL/min/kg and a Vd of 7 L/kg falls on the 8 h half-life line. Alternatively, a
combination of increasing clearance and decreasing volume of distribution might be explored.
These are fine options, but they are only helpful if we understand how to modify a lead in
order to affect clearance and volume of distribution.
Increasing clearance can be accomplished by adding functional groups that increase the
metabolic activity of the molecule. Similarly, decreasing clearance requires reactive functional
groups to be minimized. Metabolism is the topic of Chapter 8, and reactive functional groups
will be covered in that chapter.
Decreasing volume of distribution can often be achieved by making a lead more polar. A
more polar lead may be more confined to the central compartment than a highly non-polar
compound. Likewise, increasing the non-polarity of a drug tends to raise volume of
distribution. One of the parameters encountered in Lipinski's rules, lipophilicity or log P, is a
common measure of lead polarity. Log P is often tracked during a discovery program to gain
a qualitative sense of how a drug might distribute.
By guiding the discovery team on how a lead might be modified to improve it's
pharmacokinetics, a CL vs. Vd graph can be a very useful tool in drug development.