Prodrugs metabolic activation

Fig. 8.18. Metabolic activation of the prodrug molsidomine (8.159), first by enzymatic hydrolysis of the carbamic acid ester moiety to the inactive metabolite 8.160, followed by spontaneous degradation to the active metabolite 8.161, most likely an NO donor [207] [208]...

Fig. 9.14. Metabolic activation of phosphoramidic acid diester prodrugs 9.79 of stavudine (and analogous nucleosides). Carboxylesterase-mediated hydrolysis of the terminal carboxy-late is followed by spontaneous cyclization-elimination with formation of a pentacyclic mixed-anhydride species. The latter hydrolyzes rapidly to the corresponding phosphoramidic acid monoester, which can then be processed to stavudine 5 -monophosphate.

S. W. Mamber, A. B. Mikkilineni, E. J. Pack, M. P. Rosser, H. Wong, Y. Ueda, S. Fo-renza, Tubulin Polymerization by Paclitaxel (Taxol) Phosphate Prodrugs after Metabolic Activation by Alkaline Phosphatase , J. Pharmacol. Exp. Then 1995, 274, 877-883. 

Prodrugs Inactive drugs that undergo metabolic activation. 

Metabolism 5% metabolised by the liver First-pass effect Hepatocyte dependent Prodrug CYPs Active metabolites Genetics... 

It should also be noted that the activation of a mechanism-based inhibitor by its target enzyme is, formally, an example of metabolic activation. However, there is a clear distinction between the activation of a mechanism-based inhibitor described above and the metabolic activation of a prodrug. In the latter case, an inactive precursor is metabolized in the body (either chemically or enzymatically) to metabolites that possess the desired activity. For example. Acyclovir (3a) must be metabol-ically converted to the triphosphate (3b) and released into the medium before it will inhibit viral DNA polymerase. Further discussion on prodrugs may be found in volume 2, chapter 14. 

A prodrug by definition is inactive or much less active and has to be converted to the active drug within the biological system. There are a variety of mechanisms by which a prodrug can be activated. These include metabolic activation mediated by enzymes present in the biological system as well as the less common, simple chemical means of activation such as hydrolysis. 

Figure 13.44. Metabolic activation of capecitabine (50), a site-selective multistep prodrug of the antitumor drug 5-fluorouracil (5-FU) (53)Following oral absorption, the prodrug is hydrolyzed by liver carboxylesterase to a carbamic acid that spontaneously decarboxylates to 5 -deow-5-fluorocy-tidine (51). The latter is transformed into 5 -deoxy-5-fluorouridine (52) by cytidine deaminase present in the liver and tumors. The third activation step occurs selectively in tumor cells and involves the transformation to 5-FU (53), catalyzed by thymidine phosphorylase (221).

An interesting example of a DDI due to the inhibition of a non-CYP enzyme that can have serious clinical consequences is the inhibition of xanthine oxidase by allopu-rinol 6-mercaptopurine (6-MP) as an antimetabolite type of antineoplastic drug. One of its indications is in the treatment of inflammatory bowel disease. Actually, 6-MP is a prodrug whose active metabolite, 6-thiogua-nine (6-TG) is responsible for its therapeutic activity. Some nonresponders to 6-MP do not form sufficient amounts of 6-TG. A complementary pathway of 6-MP metabolism is oxidation to 6-thiouric acid (6TU), which is mediated by xanthine oxidase. Inhibition of this complementary pathway by allopurinol shunts the metabolism of 6-MP favoring increased formation of 6-TG. 

The carboxylesterase superfamily catalyzes the hydrolysis of ester- and amide-containing compounds. These enzymes are found in both the ER and cytosol of many cell types and are involved in detoxification or metabolic activation of drugs, environmental toxins, and carcinogens. Car-boxylesterases also catalyze the activation of prodrugs to their respective free acids. For example, the prodrug and cancer chemotherapeutic agent irinotecan is bioactivated by plasma and intracellular carboxylesterases to the potent topoisomerase inhibitor SN-38. 

A few compounds (prodrugs) have no activity until they undergo metabolic activation. 

Many antiviral drugs are antimetabolites that resemble the structure of naturally occurring purine and pyrimidine bases or their nucleoside forms. Antimetabolites are usually prodrugs requiring metabolic activation by host-cell or viral enzymes—commonly, such bioactivation involves phosphorylation reactions catalyzed by kinases. 

---