Even though many drugs are essentially absorbed in a complete manner from the gastrointestinal tract after oral administration many of such drugs suffer from low bioavailability due to extensive presystemic (or first-pass) metabolism before reaching the systemic circulation. Presystemic 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 metabolism by directly blocking the susceptible part of the molecule or by blocking at an alternative position 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 significantly reduced by administration of the N-(N-acetyl-L-methionyl)-0,0-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 peptides, 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 esterification 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.
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FIGURE 9.15 Bioactivation of N-(N-acetyl- L-methionyl)-0,0-biscarbonyl dopamine.
The utility of prodrugs as a means to achieve prolonged pharmacological action of a drug has been effective mainly in terms of intramuscular (IM) injection preparations and other local administrations. For oral administration, the prodrug principle has not been investigated extensively with the aim to prolong drug action and it is questionable if this approach will offer any benefit to well-established formulation principles such as matrix systems, osmotic systems, and pellet systems.
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