Source: From Ref. 91.
Source: From Ref. 91.
offer little opportunity for drug targeting. A detailed discussion of prodrugs listed in Table 3 can be found in book chapters by Stella (92) and Roche (93).
Numerous reports of prodrugs in the literature show improved drug effects. Prodrugs that have shown some measure of success for site-specific delivery include l-3,4-dihydroxyphenylalanine (l-dopa) to the brain (94), dipivaloyl derivative of epinephrine to the eye (95), y-glutamyl-l-dopa to the kidney (96), P-d-glucoside dexamethasone and prednisolone derivatives to the colon (97), thiamine-tetrahydrofuryldisulfide to red blood cells (98), and various amino acid derivatives of antitumor agents, such as daunorubicin (DNR) (99,100), acivicin (101), doxorubicin (101), and phenylenediamine (101), to tumor cells.
The selective delivery of drugs to the brain has been, and continues to be, one of the greatest challenges. Only highly lipid-soluble drugs can cross the blood-brain barrier. Prodrugs with high lipid solubility can be used, but they may show increased partitioning to other tissues and thereby cause adverse reactions. For example, l-dopa, the precursor of dopamine, when administered orally, readily partitions throughout the body, including the brain. Its conversion to dopamine in the corpus striatum produces the therapeutic response, whereas its conversion in the peripheral tissues results in many undesirable side effects. Although many of these side effects can be overcome by additional administration of an inhibitor of aromatic amino acid decarboxylase, such as carbidopa (this does not penetrate into the brain and thereby permits the conversion of l-dopa to dopamine in the brain, but prevents its transformation in the peripheral tissues), the direct delivery of dopamine to the brain constitutes an attractive alternative. One approach that has been used is a prodrug carrier system developed by Bodor and Simpkins (102). This approach is based on the observation that certain dihydropyridines readily enter the brain, where they are oxidized to the corresponding quaternary salts. The latter, owing to difficulty in crossing the blood-brain barrier, remain in the brain. The formation of quaternary salts in the peripheral tissues, on the other hand, rapidly accelerates their removal by renal or biliary mechanisms. This results in a significant buildup of the quaternary salt concentration in the brain and a significant reduction in systemic toxicity. Chemical or enzymatic hydrolysis of the quaternary salt (in the brain) then slowly releases the drug in the cerebrospinal fluid, allowing the therapeutic concentration to be maintained over some period. Examples of drugs that have been investigated using this approach include pralidoxime iodide (2-pyridine aldoxime methyl iodide) (103), phenylethylamine (104), dopamine (105), 3'-azido-2',3'dideoxyuridine (AZddU) (106), and 3'-azido-3'-deoxythymidine (AZT; zidovudine) (106-108).
Recently, new prodrug strategies aimed at targeting a specific enzyme or a specific membrane transporter or both, facilitated by simultaneous use of gene delivery engineered to express the requisite enzyme or transporter, have been developed and proposed to be especially useful in cancer chemotherapy (90).
The use of polymeric prodrugs has also been the subject of intense research recently. Various synthetic strategies to prepare prodrugs and their use in passive and active targeting have been reviewed by Khandare and Minko (109). An excellent review covering prodrugs of anthracyclines in cancer chemotherapy has been reported by Kratz et al. (110). Selected polymer-drug conjugate systems are also discussed in this chapter later.
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