Prodrugs metabolic conversion

FIGURE 1.1 Metabolic conversion of prodrugs to pharmacologically active agents. 

Mechanism of action This prodrug is transformed to the anti metabolite mercaptopurine, which upon further metabolic conversion inhibits enzymes involved in purine metabolism. Azathioprine is cytotoxic in the early phase of lymphoid cell proliferation and has a greater effect on the activity of T cells than B cells. 

Takayanta. H., Watanabe, A., Ho.sokawa. M Chiba, K Satoh. T., and Ainii, N. (1998). Synthesis of a new class of camptothecin derivatives, the long-chain fatly acid esters of lO-hydroxy-camptocheciii, as a potent prodrug candidate, and their in vitro metabolic conversion by carboxylesterases. Bioorg. Med. Otem. Let/. 8,415-418. 

These data suggest that the basis for antiviral activity of the 2,5 -anhydro nucleoside analogues does not depend on a conversion of "inactive" (anhydro) prodrug to yield an active (parent) species, but rather the anhydro compounds appear to be active per se. However, an intracellular cleavage of the 2,5 -anhydro linkage or other metabolic conversions cannot be ruled out. 

Viprostol (81) also incorporates a hydroxy group moved to C-16 and protects this from facile metabolic oxidation by vinylation. It is a potent hypotensive and vasodilatory agent both orally and transdermally. The methyl ester moiety is rapidly hydrolyzed in skin and in the liver so it is essentially a prodrug. It is synthesized from protected E-iodo olefin 78 (compare with 75) by conversion to the mixed organocuprate and this added in a 1,4-sense to olefin 79 to produce protected intermediate 80. The synthesis of viprostol concludes by deblocking with acetic acid and then reesterification with diazomethane to give 81 [19]. 

Metabolic pathways rarely lead to breaking a carbon-carbon bond however, there are exceptions such as the conversion of the prodrug nabumetone to an active nonsteroidal anti-inflammatory agent as shown in Figure 4.84 (153). Although the mechanism of this conversion is unknown, if oxidation leads to two adjacent carbonyl groups it weakens the carbon-carbon bond and further oxidation leads the rupture of this bond. 

Olmesartan medoxomil (5) is also a prodrug that is rapidly and completely bioactivated by ester hydrolysis to olmesartan (RNH-6270) during absorption from the gastrointestinal tract (Warner and Jarvis, 2002). Olmesartan is eliminated in a biphasic manner with an elimination half-life of 14 h. The absolute bioavailabihty of olmesartan is 26% and peak plasma concentration is reached in 1 -2 h. Following the rapid and complete conversion of 5 to olmesartan, there is virtually no further metabolism of olmesartan. Olmesartan is eliminated from the bile and kidneys in about a 60 40 ratio. 

Answer Famciclovir is a prodrug that is rapidly converted to penciclovir, with a bioavaUabiUty of 77%. Maximal plasma concentrations of penciclovir are reached within 45 to 60 minutes of famciclovir administration. Mr. Smith developed an allergy to topical penciclovir when he was treated with this drug during college. This prior contact sensitization to penciclovir allowed him to develop an anaphylactoid reaction following the conversion of oral famciclovir to penciclovir by hepatic first-pass metabolism. 

As a result, these subjects require twofold to threefold higher daily doses of nortriptyline (a 2D6 substrate) to achieve therapeutic plasma levels. Conversely, in these ultrarapid-metabolizing populations, the prodrug codeine (another 2D6 substrate) is metabolized much faster to morphine, often resulting in undesirable adverse effects of morphine, such as abdominal pain. 

Ultrarapid metabolism of an active drug could mean that therapeutic levels are not reached, while poor metabolism will increase the likelihood of adverse events at normal doses because of resulting increased levels of the drug. Conversely, for prodrugs that must first be activated by CYP enzymes, ultrarapid metabolism may increase adverse effects, while poor metabolism may result in little response. 

Sulindac is an inactive prodrug which needs to be converted in the liver to its active metabolite, sulindac sulfide. The metabolic pathway for sulindac is complicated, even in healthy subjects, by the reversibility of this process, the possibility of conversion to an inactive sulfone metabolite, and the extensive enterohepatic circulation of all three species [25, 26]. 

Finally, transport can also be driven by the conversion of intracellular substrate to another chemical form. For example, in the case of nucleoside drugs, conversion to the corresponding nucleotides by appropriate kinases may be the limiting factor in cellular uptake and activation. The same principle applies to sulfation, glu euro nidation, prodrug activations, or other metabolic processes that provide a removal of the transported species from the transportable (free) internal pool. In some cases, transport is directly coupled to substrate modification, as in the uptake of sugars into bacterial cells by phosphoenolpyruvate (PEP)-coupled phosphorylation systems. 

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). 

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