Carrier-linked prodrug

Classical carrier-linked prodrugs Site-specific chemical delivery systems Macromolecular prodrugs Drug-antibody conjugates... 

A special group of carrier-linked prodrugs are the site-specific chemical delivery systems [23], Macromolecular prodrugs are synthetic conjugates of drugs covalently bound (either directly or via a spacer) to proteins, polypeptides, polysaccharides, and other biodegradable polymers [24],... 

Classical carrier-linked prodrugs may sometimes be ineffective because the prodrug linkage is too stable (amides, non-activated esters). In such cases, a 3-assistance, provided... 

Numerous carrier-linked prodrugs have been prepared from drugs containing an adequate functional group. Without aiming at comprehensiveness, a list of common and less common carrier groups is given in Table 13.14 for... 

Kratz F, Ajai KA, Warnecke A (2007). Anticancer carrier-linked prodrugs in clinical trials. Expert Opin Investig Drugs 17 1037-1058. 

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... 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

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 ... 

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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