Prodrugs Transformed by Spontaneous Reactions

As an alternative to the enzymatic-mediated bioconversion, prodrugs may be designed to undergo spontaneous (or chemical) transformation dictated by the physicochemical environment such as the pH in various parts of the human body.

Some important examples of prodrugs biotransformed by nonenzymatic-mediated reactions are hydroxymethyl derivatives of NH-acidic drug molecules such as 5-fluorouracil, phenytoin, N-Mannich bases derived from drugs containing amino or amide functions (e.g., tetracycline, car-bamazepine) and ring-opened derivatives of cyclic drugs (e.g., pilocarpine Figure 9.5). The rate of spontaneous transformation of N-hydroxymethyl prodrugs of NH-acidic drugs can be predicted from the acidity (pKa) of the parent drug compound. A linear relationship between the logarithm to the half-life (log t1/2, pH 7.4, 37°C) of N-hydroxymethyl derivatives and the pKa of the parent NH-acidic drug has been established allowing easy evaluation to whether a N-hydroxymethyl derivative may consist an attractive prodrug principle for a given drug molecule:

Evaluation of N-Mannich bases as potential prodrugs for NH-acidic drugs offers considerable room for the design of appropriate characteristics with respect to lipophilicity, aqueous solubility, and biological half-life (t1/2). This is achieved by proper selection of pÀ"a and substituent pattern (Rj and R2 in Figure 9.4b) of the attached amino moiety as the rate of biotransformation is controlled by both the pÀ"a and the sterical hindrance caused by substituents connected to the amino moiety.

Nonenzymatic catalyzed bioconversion of prodrugs has the advantage that physicochemical properties such as pH in the bloodstream is predictable and show low interindividual variability leading to predictable and reliable conversion of the prodrug in vivo.

On the other hand, it should be noted that such prodrugs possess an inherent drawback in that incorporation of a chemically labile function may lead to formulation stability problems and, consequently, to reduced shelf-life. An elegant solution to this problem is the double-prodrug concept where an enzymatic-mediated transformation is combined with a subsequent spontaneous reaction releasing the active parent drug.

An example of this is the protection by acylation of very labile N-hydroxyalkyl derivatives of NH-acidic drugs with pÀ"a values below approximately 11 (t1/2 < 1 min at 37°C and pH 7.4) as illustrated in Figure 9.6. After enzymatic cleavage of the ester function the highly unstable N-hydroxyalkyl intermediate is rapidly converted into the parent HN-acidic drug molecule.


FIGURE 9.4 Schematic examples of prodrugs designed to undergo spontaneous nonenzymatic transformation.


Pilocarpic acid ester Pilocarpine

FIGURE 9.5 Pilocarpic acid ester prodrug cyclization into pilocarpine.

i\ I1 M Enzyme

W-Acyloxyalkyl prodrug

W-Hydroxyalkyl intermediate

Spontaneous (fast)

FIGURE 9.6 The double-prodrug principle.

j/ Drug

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