Drug Elimination II

Ester hydrolysis does not invariably
lead to inactive metabolites, as exemplified
by acetylsalicylic acid. The cleavage
product, salicylic acid, retains pharmacological
activity. In certain cases,
drugs are administered in the form of
esters in order to facilitate absorption
(enalapril ! enalaprilate; testosterone
undecanoate ! testosterone) or to reduce
irritation of the gastrointestinal
mucosa (erythromycin succinate !
erythromycin). In these cases, the ester
itself is not active, but the cleavage
product is. Thus, an inactive precursor
or prodrug is applied, formation of the
active molecule occurring only after hydrolysis
in the blood.
Some drugs possessing amide
bonds, such as prilocaine, and of course,
peptides, can be hydrolyzed by peptidases
and inactivated in this manner.
Peptidases are also of pharmacological
interest because they are responsible
for the formation of highly reactive
cleavage products (fibrin, p. 146) and
potent mediators (angiotensin II, p. 124;
bradykinin, enkephalin, p. 210) from
biologically inactive peptides.
Peptidases exhibit some substrate
selectivity and can be selectively inhibited,
as exemplified by the formation of
angiotensin II, whose actions inter alia
include vasoconstriction. Angiotensin II
is formed from angiotensin I by cleavage
of the C-terminal dipeptide histidylleucine.
Hydrolysis is catalyzed by “angiotensin-
converting enzyme” (ACE). Peptide
analogues such as captopril (p. 124)
block this enzyme. Angiotensin II is degraded
by angiotensinase A, which clips
off the N-terminal asparagine residue.
The product, angiotensin III, lacks vasoconstrictor
activity.