Carrier prodrugs

Carrier prodrugs are formed by combining an active drug with a carrier species to form a compound with the desired chemical and biological characteristics, for example, a lipophilic moiety to improve transport through membranes. The link between carrier and active species must be a group, such as an ester or amide, that can be easily metabolized once absorption has occurred or the drug has been delivered to the required body compartment. The overall process may be summarized by  

The choice of functional group used as a metabolic link depends both on the functional groups occurring in the drug molecule (Table 9.5) and the need for the prodrug to be metabolized in the appropriate body compartment. 

The precise nature of the structure of the carrier used to form a carrier prodrug will depend on the intended outcome (see section 9.8.3). 

Drug group (D-X) Type of group linking carrier to the drug Examples of R groups 

Alcohol, phenol (D-OH) Ester D-OCOR Alkyl, Phenyl, - (CH2)2NR2, - (CH2) CONR R , - (CH2) HCOR, CH2OCOR.  

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Odour and taste are important aspects of drug administration. A drug with a poor odour or too bitter a taste will be rejected by patients, especially children. Furthermore, a drug that causes pain when administered by injection can have a detrimental effect on a patient. The formation of a carrier prodrug can sometimes alleviate some of these problems. For example, palmitic acid and other long chain fatty acids are often used as carriers, since they usually form prodrugs with a bland taste. 

In theory, it should be possible to design a carrier prodrug that would only release the drug in the vicinity of its site of action. Furthermore, once released, the drug should remain mainly in the target area and only slowly migrate to other areas. In addition the carrier should be metabolized to nontoxic metabolites. Unfortunately, these requirements have only been achieved in a few cases. 

Carrier prodrugs result from a temporary linkage of the active molecule with a transport moiety that is frequently of lipophilic nature. A simple hydrolytic reaction cleaves this transport moiety at the correct moment (e.g. pivampicillin, bacampicillin,). Such prodrugs are, per se, less active than the parent compounds or even inactive. The transport moiety (carrier gronp) is chosen for its non-toxicity and its ability to ensnre the release of the active principle with efficient kinetics. 

A well-designed carrier prodrug satisfies the following... 

The bioavailability of carrier prodrugs is modulated by using a transient transport moiety such a linkage is not implied for bioprecursors, which result from a molecular modification of the active principle itself. 

The lipophilicity is generally the subject of a profound alteration of the parent molecule in the case of carrier prodrugs, whereas it remains practically unchanged for bioprecursors. 

The bioactivation process is exclusively hydrolytic for carrier prodrugs it involves mostly redox systems for bioprecursors. 

The catalysis leading to the active principle is hydrolytic (either through general catalysis or through extra-hepatic enzymes) for carrier prodrugs. For bioprecursors, it seems largely restricted to Phase I metabolizing enzymes. 

Wermuth, C. G., Gaignault, J.-C., Marchandeau, C. Designing prodrugs and bioprecursors 1 carrier prodrugs. In The Practice of Medicinal Chemistry (Wermuth, C. G., Ed.). Academic Press London, 1996, pp. 671-696. 

V Carrier Prodrugs Application Examples 564 XI Reactions Without Change ... 

V Use of Cascade Prodrugs 571 A Bioprecursors versus carrier prodrugs 579... 

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