Prodrugs toxic potential

The toxic potential of metabolic intermediates, of the carrier moiety, or of a fragment thereof, should never be neglected. For example, some problems may be associated with formaldehyde-releasing prodrugs such as N- and 0-[(acyloxy)methy 1] derivatives or Mannich bases. Similarly, arylacetylenes assayed as potential bioprecursors of anti-inflammatory arylacetic acids proved many years ago to be highly toxic due to the formation of an intermediate ketene. 

In summary, (oxodioxolyl)methyl esters of carboxylic acid drugs appear to be generally useful as prodrugs. However, more studies are needed to document the structure-metabolism relationships, the relative contribution of enzymatic vs. nonenzymatic reactions in their in vivo activation, the reasons of some failures, their toxic potential, and their pharmacokinetic behavior in humans. 

Pt(TV) Prodrugs. Platinum(IV) complexes have been widely studied as potential prodrugs that avoid the limitations of the cisplatin class of anticancer drugs. Indeed, the Pt(IV) compound satraplatin [Pt(cha)Cl2(OAc)2(NH3)] (cha, cyclohexylamine) is currently in clinical trials for treatment of hormone-refractory prostate cancer (Fig. 1) (22). Satraplatin is the first orally bioavailable platinum derivative under active clinical investigation and is particularly attractive because of the convenience of administration, milder toxicity profile, and lack of cross-resistance with cisplatin. These results are promising and support the idea that platinum(IV) complexes offer the opportunity to overcome some of the problems associated with cisplatin and its analogs. 

Owing to the favorable activity profile of 66, which acts as a prodrug of the active species 62, additional studies were conducted on 66 to establish its cell-based profile. It was determined that 66 potentiated chlorambucil (74) toxicity in cell lines expressing GST Pl-1, namely HT-29, HT4-1, SK OV-3, and SK VLB. Also, while 66 alone did not prevent tumor growth in the HT4-1 xenograph model, 66 increased by 56% the tumor growth inhibitory effect of melphalan (75). 

Bioprecursors provide relevant examples of chemotherapeutic agents whose activation occurs by reduction in oxygen-deprived cells. Bioprecursors certainly appear as a viable class of prodrugs, since they avoid potential toxicity problems caused by the carrier moiety (see below). In contrast, attention must be given here to metabolic intermediates. 

The regulation of drug stability can take two directions a prodrug can increase the in vivo stability of an active compound and prolong its action, or it can automatically limit its duration and prevent potential toxicity. 

A number of benzimidazoles exist as prodrugs their anthelminthic activity is due to the fact that they are metabolized in the animal body to the biologically active benzimidazole carbamate nucleus. Due to their relatively slower excretion rates, the newer insoluble benzimidazoles have fairly long withdrawal periods for edible tissues and milk in contrast to the less effective and more rapidly excreted thiabendazole analogues. Strict compliance with withdrawal periods is always necessary because of the potentially toxic and teratogenic effects of some of the benzimidazoles and their metabolites. 

Today, with the exception of bone marrow for hematopoietic reconstitution, therapeutic cellular transplantation is an emerging technology. In recent years novel approaches in the potential restoration of function through cellular transplantation have included the use of fetal human or xenogeneic neural tissue for Parkinson s disease, ectopically implanted pancreatic islets for diabetes, Schwann cells and olfactory ensheathing glia for spinal cord injury, encapsulated chromaffin cells for pain, and various types of stem cells for the treatment of diabetes, cardiac disease, and central nervous system injuries or disease [2], There have also been trials of encapsulated cells to provide enzymes that either remove toxic products or provide activation of prodrugs to therapeutics, usually anticancer derivatives. 

In contrast, many lipophilic drugs or prodrugs can only be applied therapeutically by use of potentially toxic solubilizing agents such as detergents or polymers or by development of complex pharmaceutical formulations (6-8). Therefore, in view of such... 

In general, drug metabolism serves to inactivate a substrate and increase water solubility of the substrate for excretion, bioactivate a substrate or prodrug (e.g., codeine and cyclophosphamide) to an active or mutagenic principle, or less commonly, extend the elimination half-life of a pharmacologically active or potentially toxic metabohte. Metabolic reactions are often divided into Phase I and Phase II categories, as depicted in Figure 43-1. 

A second challenge is the toxitity potential of some prodrugs, namely, a toxic metabolite formed from the promoiety or a reactive metabolic intermediate generated during the activation of some bioprecursors. The former case is illustrated by the liberation of formaldehyde, as seen with Mannich bases or some double esters [1,4]. The latter case involves a very few known examples of failed bioprecursors whose activation was via a reactive and toxic intermediate. Thus, arylacetylenes were examined as potential bioprecursors of nonsteroidal anti-inflammatory agents [1]. Although the nature of the final (and stable) metabolite (an arylacetic add) was known, researchers at the time were not aware that the metabolic pathway involved an intermediate and highly reactive ketene. 

In a review of potential hazards of the prodrug approach, Gorrod cites fom toxicity mechanisms ... 

Murdock. K.C.. Lee. V.J., Citarella, R.V., Duir, F.E., Nicolau, G., and Kohlbrenner. M., A-Phosphoryl derivatives of bisantrene. Antitumor prodrugs with enhanced solubihty and reduced potential for toxicity. J. Med. Chem., 36, 2098, 1993. 

Fluorinated antipyrimidine analog of uracil prodrug fluorodeoxyuridine monophosphate (FdUMP) is active form thymidylate synthase (TS) inhibitor interferes with RNA/DNA function "false" pyrimidine leucovorin enhances binding of FdUMP to TS potentiates cytotoxicity as well as toxicity cell-cycle specific S phase... 

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