Prodrugs Transformed by Enzymatic Reactions

Prodrugs can be designed to target specific enzymes in the body. This is based upon knowledge and considerations on enzyme activity, specificity, tissue distribution, and abundance and can be utilized to obtain the desired ability of a prodrug to overcome one or more barriers to development of the active drug molecule.

The most common prodrugs are those requiring hydrolytic cleavage mediated by enzymatic catalysis. Drugs containing hydroxyl, carboxyl, or amino functional groups can be converted into prodrug esters or amides from which the active forms are readily regenerated by hydrolytic enzymes such as esterases (see Section 9.4.1.2), amidases, peptidases, or phosphatases (see Section 9.4.1.1) (Figure 9.3).

Less often prodrugs are designed to undergo reductive or oxidative processes mediated by enzymes such as cytochrome P450, monoamine oxidases, azoreductases (see Section 9.4.3), or nitroreductases. A novel prodrug principle (HepDirectâ„¢) has recently been introduced for highly site-specific delivery of phosphate drugs to the liver. These prodrugs consist of cyclic 1,3-propanyl esters

O II

O II

O II

Esterase

Esterase

Amidase

Phosphatase ->-

O II

O II

0 II

FIGURE 9.3 Schematic examples of prodrugs designed to undergo enzymatic-mediated hydrolysis.

of phosphates designed to undergo enzyme-catalyzed oxidative conversion into active phosphates specifically mediated by CYP3A4 enzymes present in the liver.

A challenge in the design of prodrugs susceptible to enzymatic conversion is the limited availability of predictive in vitro and in vivo models for selection and optimization of the prodrug candidate. In vitro assays in which reaction kinetics is studied in the presence of human or animal material such as blood, serum, plasma, and intestinal or liver tissue can provide qualitative information on drug conversion whereas to a much lesser extent they offer quantitative predictions on the rate and extent to which biotransformation takes place in vivo. In vivo models using experimental animals such as mice, rats, dogs, or monkeys can indeed provide in vivo relevant information but suffers from the only sparse knowledge available on species differences in terms of enzyme abundance, distribution, activity, and specificity compared to the human in vivo situation. Thus, there is a risk that prodrugs dependent on bioconversion mediated by enzymes may show high interindividual variability due to variability in enzyme levels and activity between individuals.

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