Prodrugs active drug release

In addition to nitrobenzyl carbamate prodrugs, some nitro heteroaromatic prodrugs have also been reported. Scheme 7 shows the general mode of active drug release.33-36... 

An interesting example of the above difference is l-DOPA 4, which is used in the treatment of Parkinson s disease. The active drug is the achiral compound dopamine formed from 4 via in vivo decarboxylation. As dopamine cannot cross the blood-brain barrier to reach the required site of action, the prodrug 4 is administered. Enzyme-catalyzed in vivo decarboxylation releases the drug in its active form (dopamine). The enzyme l-DOPA decarboxylase, however, discriminates the stereoisomers of DOPA specifically and only decarboxylates the L-enantiomer of 4. It is therefore essential to administer DOPA in its pure L-form. Otherwise, the accumulation of d-DOPA, which cannot be metabolized by enzymes in the human body, may be dangerous. Currently l-DOPA is prepared on an industrial scale via asymmetric catalytic hydrogenation. 

Many therapeutic agents are administered in a chemically modified form to improve features such as their solubility characteristics, ease of administration and bioavailability (Bowman and Rand, 1988). Such a prodrug must be designed to break down in vivo to release the active drug, sometimes at a... 

In the design of drugs, the usefulness of renal-specific enzymes which enable the site-specific release of the active drug, should be taken into account. The design of kidney-selective prodrugs is based upon the relatively higher amounts of certain enzymes in the proximal tubular cells than elsewhere in the body. 

Bodor and Brewster (1983) first used the term CDS, in describing the use of dihydropyridine ester- (or amide)-linked prodrugs such as 27 (X-OH is the parent) which can partition readily into the CNS, there to be oxidized to pyridinium salts (28), which are effectively trapped in the biophase because of their extreme polarity, and which then undergo enzymic or chemical hydrolysis of the now very labile ester link to release active drug. 

Tazarotene (2) is a prodrug. A prodrug is defined as a pharmacologically inactive chemical derivative of a drug molecule that requires a transformation within the body in order to release the active drug. In this particular case, the ethyl ester moiety is readily hydrolyzed by an esterase on skin to release the active metabolite, tazarotenic acid (11). Tazarotene (2) has a half-life of 2-18 min. and is rapidly cleared on skin. 

Prodrugs are drug substances that are biotransformed in the body to active metabolites and chemotherapeutic agents. Examples include sulfasalazine to sul-fapyridine, phenylbutazone to oxy-phenbutazone, aspirin to salicylate, and heta-cillin to ampicillin. In some cases, such as aspirin (ester) and hetacillin (amide), hydrolysis in water releases the active drug moiety contained within the basic structure of the prodrug. 

Subcellular localization studies have identified P-450-dependent monooxygenase activity in adult hairless mice sebaceous glands. Phase II conjugation pathways have also been identified in skin. Extracellular enzymes including esterases are present in skin, which has been utilized to formulate lipid-soluble ester prodrugs which penetrate the stratum corneum and then are cleaved to release active drug into the systemic circulation. Finally, co-administration of enzyme inducers and inhibitors modulate cutaneous biotransformation and thus alter the systemic toxicity profile. These metabolic interactions that occur in skin have attracted a great deal of research attention and clearly illustrate that skin is more than a passive barrier to toxin absorption. 

When the transdermal penetration of a drug is inadequate to achieve and maintain a plasma concentration above the minimum therapeutic concentration required to produce the desired effect, a lipophilic prodrug that will be metabolized in the epidermis to the active drug could be used in the development of a controlled-release transdermal delivery system. This approach has been applied to estradiol esters (diacetate and valerate) which are rapidly converted by esterases in the skin tissue to estradiol (Chien et al, 1985). The prodrug serves to increase the transdermal bioavailability of the active drug to which it is converted by metabolism (generally ester hydrolysis) during the percutaneous absorption process. 

A pro-drug is a substance that has no special biological activity per se but can be converted into an active drug by enzymic action in the body. Thus, all the initial proteins formed by ribosomal synthesis that contain a peptide hormone structure locked within their amino-acid sequence are analogous to pro-drugs. The hormones are released by the action of proteolytic enzymes. Usually, however, the term prodrug is restricted to artificially synthesised molecules that are acted upon by the... 

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