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

MOOC Medicinal Chemistry
MOOC Medicinal Chemistry