Prodrugs site activation

Tissue-selective activation of classical prodrugs Site-specific delivery of ad hoc chemical systems... 

Classical carrier-linked prodrugs Site-specific chemical delivery systems Macromolecular prodrugs Drug-antibody conjugates Mechanisms of activation Enzymatic... 

The selective reconversion of the prodrug to the active moiety at the target relative to its cleavage at other sites in the body... 

Drugs may also undergo hydrolysis by intestinal esterases (hydrolases), more specifically carboxylesterases (EC 3.1.1.1) in the intestinal lumen and at the brush border membrane [58, 59]. It has been shown that intestinal hydrolase activity in humans was closer to that of the rat than the dog or Caco-2 cells [60]. In these studies, six propranolol ester prodrugs and p-nitrophenylacetate were used as substrates, and the hydrolase activity found was ranked in the order human > rat Caco-2 cells > dog for intestinal microsomes. The rank order in hydrolase activity for the intestinal cytosolic fraction was rat > Caco-2 cells = human > dog. The hydrolase activity towards p-nitrophenylacetate and tenofovir disoproxil has also been reported in various intestinal segments from rats, pigs and humans. The enzyme activity in intestinal homogenates was found to be both site-specific (duodenum > jejunum > ileum > colon) and species-dependent (rat > man > Pig)-... 

NB2001 (23), a prodrug of triclosan, has been developed based on the enzyme-catalyzed therapeutic activation (ECTA) concept. Evidence supporting ring opening of the cephalosporin moiety by penicillin-binding proteins and/ or (3-lactamases to release triclosan at the bacterium site, as well as sub-pg/mL MIC on [3-lactamase-positive strains, demonstrates the potential of this approach [42]. 

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. 

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