Reversible prodrug form

TABLE 8.1 Reversible Prodrug Forms for Various Functional Groups Present in Biologically Active Substances... 

Prodrug approaches have been used to increase the oral bioavailabilities of cephalosporins. Ester prodrugs are formed by reversible esterification of the carboxyl group on these antibiotics [20], These prodrugs are more orally bio-... 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

Methylprednisolone acetate (MPA) is a synthetic corticosteroid produced as the 6a-methyl derivative of prednisolone. Pharmacological studies of the esters of MPA show that it is rapidly converted to methylprednisolone, the active form. Reversible metabolism of methylpredniso/o to methyl-prednisoMC creates the inactive metabolite. The conversion from the prodrug to the active form of the drug is partially responsible for variations identified in the classification of the duration of MPA activity. High levels of the active product, methylprednisolone, have been identified in synovial fluid within 2 h of MPA injection. Despite the persistence of MPA levels for 5-39 days after injection, the active metabolite was only identifiable for 2-6 days (Auteflage et al 1986). 

Schiff Bases and Oximes Schiff bases and oximes formed from ketones or aldehydes with amines or hydroxyl amines are chemically reversible under acidic or basic conditions. They could be used as prodrugs of compounds containing either an amine or carbonyl functionality. 

The L enantiomers of 3TC and FTC are phosphorylated faster than tlie D enantiomers. The l fonns are not substrates for cytidine deaminase whereas the D forms are. " 3TC and FTC, as well as other anti HIV nucleosides, are prodrugs that must be activated to the triphosphate level before they can inhibit reverse transcriptase in the infected cell. 

ANTIPROTOZOAL EFFECTS Melarsoprol is a prodrug that is metabolized rapidly (t j of 30 minutes) to melarsen oxide, the active form. Arsenoxides react avidly and reversibly with sulfhydryl groups and thereby inactivate many enzymes. Melarsoprol reacts with trypanothione to form melarsen oxide-trypanothione adduct, which potently inhibits trypanothione reductase. Both the sequestering of trypanothione and the inhibition of trypanothione reductase are expected to have lethal consequences to the cell, but this remains unproven. 

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