Prodrugs toxic metabolites

In summary, capecitabine (1), an A -carbamate pyrimidine nucleoside prodrug of cytotoxic antimetabolite 5-fluorouracil, is an FDA-approved anticancer drug that can be administered orally. This compound uses a multilayer of prodrug strategies that not only avoids side effects arising from exposure of toxic metabolites to healthy tissue but is converted to 5-fluorouracil only by enzymes preferentially expressed in many cancer cell types, thus resulting in selective delivery of the drug to tumors. Capecitabine is marketed under the trade name of Xeloda for use in the treatment of metastatic colorectal and breast cancers and metastatic breast cancer that is resistant to paclitaxel or anthracycline therapies. 

Many successes have been recorded in prodrug design, and a large variety of such compounds have proven their therapeutic value. Several complementary viewpoints can be adopted when addressing prodrugs, namely, their chemical classification, their mechanism of activation (i.e., enzymatic and/or non-enzymatic), their tissue selectivity, the possible production of toxic metabolites, and the gain in therapeutic benefit (Table 2). 

USA). Phenacetin is the prodrug of paracetamol, and has known toxic actions in uncontrolled general use - principally renal and hepatic toxic actions, and propensity to cause methaemoglobinaemia. However, now that paracetamol is in uncontrolled general use, it too has proved to have renal and hepatic toxic actions, especially in overdose and largely due to production of a toxic metabolite N-acetyl-p-benzoquinone. Paracetamol is an effective weak analgesic that does not cause gastric irritation, and is a useful... 

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 contrast to UGTlA-related irinotecan toxicity, where low enzyme activity results in prolonged exposure to a toxic metabolite, another common chemotherapeutic agent, tamoxifen, has received recent attention for the role of specific enzymes in conversion of this prodrug to its active metabolites. The second part of this article discusses the elfects of CYP variants on tamoxifen therapy. 

Formation of a toxic metabolite of the total prodrug, which is not produced by the parent drug. 

Minoxidil is extremely efficacious and is thus reserved for severe hypertension. Minoxidil is a prodrug its metabolite, minoxidil sulfate, is a potassium channel opener that hyperpolarizes and relaxes vascular smooth muscle. The toxicity of minoxidil consists of severe compensatory responses (Table 11-2, Figure 11-2), hirsutism, and pericardial abnormalities. 

Hemorrhagic cystitis, myelosuppression. IV. Prodrug is metabolized to cytotoxic derivatives. Germ cell testicular cancer, others under investigation. Mesna is coadministered. It binds to toxic metabolites of ifosphamide, thus decreasing side effects. 

Nifurtimox, a nitrofuran, is a prodrug that is reduced to unstable nitroanion radicals, which react to produce highly toxic oxygen metabolites, such as superoxide and peroxide. Oxidative stress subsequently kills the parasite, which seems to lack effective enzymatic pathways to detoxify oxygen metabolites. 

In the above-mentioned examples, the prediction of CYP-mediated compound interactions is a starting point in any metabolic pathway prediction or enzyme inactivation. This chapter presents an evolution of a standard method [1], widely used in pharmaceutical research in the early-ADMET (absorption, distribution, metabolism, excretion and toxicity) field, which provides information on the biotransformations produced by CYP-mediated substrate interactions. The methodology can be applied automatically to all the cytochromes whose 3 D structure can be modeled or is known, including plants as well as phase II enzymes. It can be used by chemists to detect molecular positions that should be protected to avoid metabolic degradation, or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early-ADMET where metabolite- or mechanism based inhibition (MBI) must be evaluated as early as possible. 

Acetaminophen is one of the most important drugs used in the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary. Phenacetin, a prodrug that is metabolized to acetaminophen, is more toxic than its active metabolite and has no rational indications. 

Although initially and abortively developed for treatment of HIV infection, adefovir dipivoxil gained approval, at lower and less toxic doses, for treatment of HBV infection. Adefovir dipivoxil is the diester prodrug of adefovir, an acyclic phosphonated adenine nucleotide analog (Rgure 49-2). It is phosphorylated by cellular kinases to the active diphosphate metabolite and then competitively inhibits HBV DNA polymerase to result in chain termination after incorporation into the viral DNA. Adefovir is active in vitro... 

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. 

Originally developed for chemotherapy, azathioprine is used today mainly as an immunosuppressive agent and rarely as an antineoplastic drug. It was introduced as an immunosuppressive agent by a British pioneer of tissue transplantation, Roy Caine. Azathioprine was used to prevent rejection after tissue transplantation as a replacement for 6-mercaptopurine because it was less toxic. In addition to tissue transplantation, it is also used for rheumatoid arthritis and Crohn s disease. Azathioprine is a prodrug which in the body is converted to its active metabolites 6-mercaptopurine and 6-thioinosinic acid. Until the discovery of cyclosporine, azathioprine in combination with steroids was the standard treatment to prevent rejection after tissue transplantation. 

A prodmg is a pharmacacologically inactive compound which undergoes chemical or enzymatic metabolism to the active. Some of the early pharmaceuticals were found to be prodrugs and this finding has led to the subsequent introduction of the metabolite itself into therapy, particularly in cases where the active metabolite is less toxic or has fewer side-effects than the parent prodmg. The administration of the active metabolite may also reduce variability in clinical response between individuals due to differences in pharmacogenetics. 

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