Biomedical Engineering Reference
In-Depth Information
Old paradigm
New paradigm
Drug discovery
Drug development
Drug discovery and early development
Eicacy
Eicacy
Drugability
Drugability
Safety
Safety
FIGURE 9.1
Shift in drug discovery/drug development paradigm.
In the new paradigm, an integrated approach to drug design is introduced that takes into account
optimization of lead compounds based upon both pharmacological (afi nity and specii city), ADME
(clearance, metabolic enzymes, and protein binding) and biopharmaceutical (lipophilicity, cell
membrane permeability), as well as pharmaceutical (solubility, physical and chemical stability)
properties. This is illustrated in Figure 9.1.
However, with the integrated approach it may still prove to be a Herculean task to compress all
the desired characteristics of efi cacy, safety, and drugability into a single molecule. One poten-
tial solution to this challenge is the utilization of the prodrug principle as part of drug design and
discovery.
9.2
THE PRODRUG PRINCIPLE
The term “prodrug” or “proagent” was introduced by A. Albert in 1958 to describe compounds that
undergo biotransformation prior to eliciting a pharmacological effect.
As shown in Figure 9.2, the formation of a prodrug provides a transient change of physicochemi-
cal and biological properties thereby altering or eliminating undesirable properties of the parent
drug molecule. This prodrug to drug biotransformation may take place before absorption, during
absorption, immediately after absorption, or at a specii c site of action.
The conversion of prodrugs to the active parent drug molecule can take place through various
reactions such as hydrolytic cleavage either as a spontaneous or enzyme-mediated reaction.
B
A
R
R
I
E
R
Drug
Drug
Chemical
modiication
Transformation
Prodrug
Prodrug
FIGURE 9.2
The prodrug principle.
