Biomedical Engineering Reference
In-Depth Information
metabolism may occur in the gastrointestinal tract and/or in the liver and may not only cause low
oral bioavailability but also high interindividual variability leading to suboptimal dosing, and
in some cases close monitoring of drug plasma levels in patients. Further, extensive presystemic
metabolism may lead to high amounts of various metabolites in the systemic circulation leading to
unwanted pharmacological effects or side effects.
Presystemic metabolism may be avoided or decreased by other routes of administration than
the oral routes such as inhalation, sublingual, topical, and rectal. However, as patients prefer the
oral route of administration efforts to reduce or eliminate presystemic metabolism by the prodrug
approach have been made although with limited success.
In principle, the prodrug approach can be applied to protect a drug against presystemic metabo-
lism by directly blocking the susceptible part of the molecule or by blocking at an alternative posi-
tion of the molecule. In both cases, a prodrug that is not a substrate for the metabolizing enzyme
may be obtained.
Drugs such as dopamine, morphine, isoprenaline, naltrexone, and b-oestradiol contain one or more
phenol moieties, which are generally extensively metabolized in various conjugation reactions.
Presystemic metabolism of dopamine involve O-sulfation, O-glucuronidation, O-methylation as
well as deamination and is signii cantly reduced by administration of the
N
-(
N
-acetyl-l-methionyl)-
O
,
O
-biscarbonyl derivative (Figure 9.15). In this derivative not only the phenolic groups but also the
amino moiety is protected against presystemic metabolism. The oral bioavailability of the prodrug
in dogs was increased about fourfold when compared to the parent dopamine and at the same time
the amount of metabolites in the systemic circulation was reduced.
Another group of compounds that suffer from high presystemic metabolism is the bioactive pep-
tides, which also possess suboptimal properties in terms of biomembrane permeation characteristics.
Thus, the ideal prodrug candidate for such compounds should not only protect the parent peptide
against presystemic metabolism but at the same time provide enhanced biomembrane penetration.
This has been attempted for various smaller peptides such as enkephalins and desmopressin. Cyclic
prodrugs of enkephalins have been suggested and for desmopressin derivatization of the phenolic
moiety of tyrosine by esterii cation has been reported. From these studies, it was shown that prodrug
formation provides protection against degradation by peptidases and increased the amount of parent
drug transferred from the apical to the basolateral side of the Caco-2 cell monolayer system.
CH
3
CH
2
OCO
NHCOCHCH
2
CH
2
SCH
3
CH
3
CH
2
OCO
NHCOCH
3
HO
NHCOCHCH
2
CH
2
SCH
3
HO
NHCOCH
3
HO
NH
2
HO
FIGURE 9.15
Bioactivation of
N
-(
N
-acetyl- l-methionyl)-
O
,
O
-biscarbonyl dopamine.
