6-Mercaptopurine toxicity

Azathiopurine, mercaptopurine Allopurinol Xanthine oxidase Azathiopurine/mercaptopurine toxicity... 

Mercaptopurine [P] Decreased mercaptopurine metabolism resulting in increased mercaptopurine toxicity. 

The daily dose of allopurinol is 300-600 mg. In combination with benzbromarone, the daily allopurinol dose is reduced to 100 mg. In general, allopurinol is well tolerated. The incidence of side effects is 2-3%. Exanthems, pruritus, gastrointestinal problems, and dty mouth have been observed. In rare cases, hair loss, fever, leukopenia, toxic epidermolysis (Lyell syndrome), and hqDatic dysfunction have been reported. Allopurinol inhibits the metabolic inactivation of the cytostatic dtugs azathioprine and 6-mercaptopurine. Accordingly, the administered doses of azathioprine and 6-mercaptopurine must be reduced if allopurinol is given simultaneously. 

Evans WE, Horner M, Chu YQ et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr 1991 119 985-989. 

The immunosuppressive agents (azathioprine and mercaptopurine) are generally limited to use in patients not achieving adequate response to standard medical therapy, or to reduce steroid doses when toxic doses are required. The usual dose of azathioprine is 2 to 3 mg/kg/day and 1 to 1.5 mg/kg/day for mercaptopurine. Up to 3 to 4 months may be required to observe a response. Starting doses are typically 50 mg/day and increased at 2-week intervals while monitoring complete blood count with differential. 

Increased risk of hydralazine-induced lupus, increased levels of isoniazid with an increased risk of neurotoxicity, increased risk of bladder cancer in individuals exposed to aromatic amines Increased risk of serious toxicity to mercaptopurine and azathioprine... 

The number of drugs susceptible to S-methylation is still limited but greater than the number turned over by COMT. Thiopurine methyl transferase (TPMT) is an important enzyme responsible for detoxifying mercaptopurine—a drug used to treat leukemia— as well as azathioprine —a prodrug that is metabolized to mercaptopurine (Fig. 7.12). This enzyme is polymorphic and patients who are homozygous for the deficient enzyme experience severe toxicity when given usual doses of mercaptopurine (19). Similar aromatic and heterocyclic sulfhydryls can also be substrates for TPMT. The similar thiol... 

Thiopurine methyltransferase methylates 6-mercaptopurine, a commonly used treatment for childhood acute lymphocytic leukemia, reducing its conversion to the active form of the drug. Approximately 10% of patients have intermediate enzyme activity, and 0.3% are deficient for TPMT activity. Intermediate activity patients have a greater incidence of thiopurine toxicity, whereas TPMT-deficient patients have severe or fatal hematological toxicity from 6-mercaptopurine therapy. In one study, patients deficient for TPMT tolerated only 7% of a 2.5-yr mercaptopurine treatment regimen. Patients with intermediate TPMT activity tolerated 65% of total weeks of therapy and patients with normal TPMT activity tolerated 84% of total weeks of therapy (3). 

There are several known polymorphisms in TPMT (4). Alleles TPMT 2, TPMT 3A, and TPMT 3C account for up to 95% of reduced TPMT activity. Patients heterozygous for these alleles have intermediate TPMT levels (5), and patients homozygous for the variant TPMT alleles are at high risk for severe, sometimes life-threatening, toxicity requiring significant reductions in mercaptopurine doses (5). 

Cysteine-S-conjugates have also been proposed as kidney-selective pro-drugs. Renal metabolism of S-6-(purinyl)-L-cysteine resulted in the formation of 6-mercaptopurine by the action of P-lyase [51]. However, besides formation of the intended parent compound, other S-conjugates may be formed by various radical reactions, which may induce renal toxicity. 

The reason for the selective toxicity of 6-mercaptopuiine remains to be established, but two factors may be of primary importance. 6-Mercaptopurine is anabolized primarily, if not exclusively, to the monophosphate level, and it is readily catabolized by xanthine oxidase, an enzyme that is low in most cancer cells compared to normal cells. Another factor that must be considered is the metabolic state of the target cells. Actively proliferating leukaemia cells are more sensitive to 6-mercaptopurine, as they are to all antimetabolites, than cells in the so-called Gq or stationary phase. Although this does not explain the difference between 6-mercaptopurine and other purine analogues, it may explain the ineffectiveness of 6-mercaptopurine against solid tumours, most of the cells of which are in the non-dividing state. 

Thioguanine is 5-30 times as toxic to rodents (depending on schedule) as 6-mercaptopurine and somewhat more effective against rodent neoplasms. 

Mercaptopurine is generally well tolerated. Adverse effects include bone marrow depression, anorexia, nausea, vomiting and sometimes jaundice associated with hepatic toxicity. 

Since allopurinol is metabolized by the hepatic microsomal drug-metabohzing enzymes, coadministration of drugs also metabohzed by this system should be done with caution. Because allopurinol inhibits the oxidation of mercaptopurine and azathioprine, their individual administered doses must be decreased by as much as 75% when they are given together with allopurinol. Allopurinol may also increase the toxicity of other cytotoxic drugs (e.g., vidarabine). The actions of allopurinol are not antagonized by the coadministration of salicylates. 

Myelosuppression, with leukopenia and thrombocytopenia appearing 7 to 10 days after treatment, and mild nausea are the most common adverse effects. Liver toxicity with jaundice has been reported in some patients but appears to be less common than with mercaptopurine. 

The major toxicities of mercaptopurine are myelosuppression, nausea, vomiting, and hepatic toxicity. 

Vora A, Mitchell CD, Lennard L et al. Medical Research Council. National Cancer Research Network Childhood Leukaemia Working Party. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia a randomised trial. Lancet 2006 368 1339-1348. 

Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol 1989 7 1816-1823. Erratum itv.JClin Oncol 1990 8 567. Lennard L, Lewis IJ, Michelagnoli M et al. Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia 6-mercaptopurine dosage strategies. MedPediatr Oncol 1997 29 252-255. Lennard L, Van Loon JA, Weinshilboum RM. Pharmaeogenetics of acute azathioprine toxicity relationship to thiopurine methyltransferase genetic polymorphism. Clin Pharmacol Ther 1989 46 149-154. 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

MP is converted to an inactive metabolite (6-thiouric acid) by an oxidation reaction catalyzed by xanthine oxidase, whereas 6-TG undergoes deamination. This is an important issue because the purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently used as a supportive care measure in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis. Because allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of mercaptopurine must be reduced by 50-75%. In contrast, such an interaction does not occur with 6-TG, which can be used in full doses with allopurinol. 

Azathioprine is well absorbed from the gastrointestinal tract and is metabolized primarily to mercaptopurine. Xanthine oxidase splits much of the active material to 6-thiouric acid prior to excretion in the urine. After administration of azathioprine, small amounts of unchanged drug and mercaptopurine are also excreted by the kidney, and as much as a twofold increase in toxicity may occur in anephric or anuric patients. Since much of the drug s inactivation depends on xanthine oxidase, patients who are also receiving allopurinol (see Chapters 36 and 54) for control of hyperuricemia should have the dose of azathioprine reduced to one-fourth to one-third the usual amount to prevent excessive toxicity. 

The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression, usually manifested as leukopenia, although anemia and thrombocytopenia may occur. Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur, with the gastrointestinal symptoms seen mainly at higher dosages. Flepatic dysfunction, manifested by very high serum alkaline phosphatase levels and mild jaundice, occurs occasionally, particularly in patients with preexisting hepatic dysfunction. 

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