Carrier moiety, prodrugs

Bioprecursors provide relevant examples of chemotherapeutic agents whose activation occurs by reduction in oxygen-deprived cells. Bioprecursors certainly appear as a viable class of prodrugs, since they avoid potential toxicity problems caused by the carrier moiety (see below). In contrast, attention must be given here to metabolic intermediates. 

The toxic potential of metabolic intermediates, of the carrier moiety, or of a fragment thereof, should never be neglected. For example, some problems may be associated with formaldehyde-releasing prodrugs such as N- and 0-[(acyloxy)methy 1] derivatives or Mannich bases. Similarly, arylacetylenes assayed as potential bioprecursors of anti-inflammatory arylacetic acids proved many years ago to be highly toxic due to the formation of an intermediate ketene. 

Fig. 9.8 presents another, more complex type of phosphate prodrugs, namely (phosphoryloxy)methyl carbonates and carbamates (9-26, X = O or NH, resp.) [84], Here, the [(phosphoryloxy)methyl]carbonyl carrier appears quite versatile and of potential interest to prepare prodrugs of alcohols, phenols, and amines. The cascade of reactions leading from prodrug to drug as shown in Fig. 9.8 involves three steps, namely ester hydrolysis, release of formaldehyde, and a final step of carbonate hydrolysis (X = O) or A-decar-boxylation (X = NH). Three model compounds, a secondary alcohol, a primary aliphatic amine, and a primary aromatic amine, were derivatized with the carrier moiety and examined for their rates of breakdown [84], The alcohol, indan-2-ol, yielded a carrier-linked derivative that proved relatively... 

The prodrug and the carrier moiety" should be nontoxic. Relatively "safe" moieties include amino acids, short to medium length alkyl esters, and some of the macromolecules described previously. 

The phthalimidomethyl moiety in 8.59 is another carrier examined during the design of prodrugs of nonsteroidal anti-inflammatory acids [72], The pro-... 

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 ... 

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. 

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. 

Menthol (3-glucoside is a water-soluble, non-irritating prodrug of menthol that can be used, like glucovaniUin, the 3-D-glucoside of vanillin, as a pharmaceutic flavor adjuvant. The use of sugar moieties as drug carriers has been reviewed by Chavis and Imbach. ... 

This clearly indicates that the nature of the bond between the carrier and the active moiety plays a major role in prodrug design and that pharmacokinetic considerations are of utmost importance in this context. In the following paragraphs, some typical kinds of chemical bonds are discussed. It is not intended here to present an overview on this subject, but only to give some examples of how chemistry and pharmacokinetics interact in the field of prodrugs. 

Such compounds can also be considered as carrier prodrugs, in so far as the thiolate is linked to an n-propylthio (a) or a tetrahydrofuranylmethylenethio (b) transport moiety, or as bioprecursors, in so far as a bioreductive... 

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