Esterbased prodrugs

Owing to the properties of carbonyl group, esters generally are more hydrophobic (and consequently more lipophilic) than their parent compounds. Using specifics of their chemical structure, properties of ester prodrugs can be broadly modulated to achieve particular stability and solubility profiles, provide good transcellular absorption, resist hydrolysis during the initial phase of absorption, and transform rapidly and efficiently at the site of action.18-21 Biotransformation of an ester prodrug to its active form usually involves enzymatic or nonenzymatic hydrolysis; in many cases the initial enzymatic cleavage is followed by nonenzymatic rearrangement. Ester prodrugs can be designed with single or multiple functional groups. Some examples are shown in Table 3.2.

Ester prodrugs often are designed for absorption enhancement by introducing lipophilicity and masking ionization groups of an active compound. For example, valacyclovir, the L-valyl ester prodrug of acyclovir used for treatment of herpes, demonstrates an oral bioavailability that is three to five times greater than its parent compound.24,25 The prodrug structure, shown in Fig. 3.1, is responsible for the enhanced carrier-mediated intestinal absorption via the hPEPTl peptide transporter.26 Rapid and complete conversion of valacyclovir to acyclovir results in higher plasma concentrations, allowing for reduced dosing frequency.

Similarly, oral absorption, as well as transdermal penetration, of the long-acting angiotensin-converting enzyme (ACE) inhibitor enalaprilat is improved considerably by esterification of one of its carboxyl groups. The improved pharmacokinetic properties are attributed to the significantly higher lipophilicity of the ethyl ester prodrug enalapril (Fig. 3.2)27

Ester prodrugs are also designed to reduce side effects28 by changing the physicochemical properties of active compounds that cause tissue irritation. For example, piroxicam, a nonsteroidal anti-inflammatory drugs (NSAID), is well absorbed after oral administration but causes gastrointestinal (GI) bleeding, perforation, and ulceration. Ampiroxicam (Fig. 3.3), a nonacidic prodrug, is an ester carbonate prodrug of piroxi-cam with comparable therapeutic efficacy to piroxicam and reduced ulcerogenic and GI side effects.

Another application of ester prodrugs is related to stability improvement of parent compounds by modifying particularly unstable functional groups present in active agents.29 For example, potassium tricyclo[5.2.1.0(2,6)]-decan-8-yl dithiocarbonate (D609) is a selective antitumor agent, potent antioxidant, and cytoprotectant. D609 has a strong potential to be developed as a unique chemotherapeutic agent

TABLE 3.2 Examples of Ester Prodrugs

General design objective

Improvement of physicochemical properties

Improvement of pharmacokinetic properties

Goal

Improve taste

Improve taste

Decrease pain on injection Increase solubility Increase solubility

Decrease solubility

Improve absorption

Improve absorption Target to specific transporters Increase duration of action Increase oral absorption Extend duration

Increase site specificity Decrease side effects

Drug

Chloramphenicol

Clindamycin

Clindamycin

Palcitaxel Prednisolone

Erythromycin

Adefovir

Ro-64-0802 Dopamine

Doxorubicin

Ampicillin

Fluphenazine

Dromostanolone

Aspirin and ^-acetyl-p-aminophenol

Prodrug Chloramphenicol palmitate22

Clindamycin palmitate30 Clindamycin phosphate30 PEG-Palcitaxel23 Prednisolone sodium

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