Mercaptopurine metabolism

Rees CA, Leonard L, Lilleyman JS et al. Disturbance of 6-mercaptopurine metabolism by cotrimoxazole in childhood lymphoblastic leukaemia. Cancer Chemother Pharmacol 1984 12 87-89. 

Allopurinol, a xanthine oxidase inhibitor used for the treatment of gout, inhibits metabolism of 6-mercaptopurine and other drugs metabolized by this enzyme. A serious drug interaction results from the concurrent use of allopurinol for gout and 6-mercaptopurine to block the immune response from a tissue transplant or as antimetabolite in neoplastic diseases. In some cases, however, allopurinol is used in conjunction with 6-mercaptopurine to control the increase in uric acid elimination from 6-mercaptopurine metabolism. The patient should be supervised closely, because when given in large doses, allopurinol, an inhibitor of purine metabolism, may have serious effects on bone marrow. 

Cuffari C, Theoret Y, Latour S, et al. 6-Mercaptopurine metabolism in Crohn s disease correlation with efficacy and toxicity. Gut 1996 39 401-406. 

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. 

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. 

Lilleyman JS, Lennard L. Mercaptopurine metabolism and risk of relapse in ehildhood lymphoblastie leukaemia. Lancet 1994 343 1188-1190. 

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

Stocco G, Cheok MH, Crews KRet al (2009) Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther 85 164-172... 

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. 

There are several important drug-drug interactions with allopurinol. The effects of both theophylline and warfarin may be potentiated by allopurinol. Azathioprine and 6-mercaptopurine are purines whose metabolism is inhibited... 

Mercaptopurine (6-MP) is an oral purine analog that is converted to a ribonucleotide to inhibit purine synthesis. Mercaptopurine is converted into thiopurine nucleotides, which are catabolized by thiopurine S-methyltransferase (TPMT), which is subject to genetic polymorphisms and may cause severe myelosuppression. TPMT status may be assessed prior to therapy to reduce drug-induced morbidity and the costs of hospitalizations for neutropenic events. Mercaptopurine is poorly absorbed, with a time to peak concentration of 1 to 2 hours after an oral dose. The half-life is 21 minutes in pediatric patients and 47 minutes in adults. Mercaptopurine is used in the treatment of acute lymphocytic leukemia and chronic myelogenous leukemia. Significant side effects include myelosuppression, mild nausea, skin rash, and cholestasis. When allopurinol is used in combination with 6-MP, the dose of 6-MP must be reduced by 66% to 75% of the usual dose because allopurinol blocks the metabolism of 6-MP. 

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... 

I. Y. Hwang, A. A. Elfarra, Cysteine S-Conjugates May Act as Kidney-Selective Prodrugs Formation of 6-Mercaptopurine by the Renal Metabolism of, V-(6-Purinyl)-i,-cysteine , J. Pharmacol. Exp. Ther. 1989, 251, 448 - 454. 

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. 

Although demethylation, which occurs in the liver, is normally considered to be a catabolic process, it may result in conversion of an inactive form of a drug to the active form. Thus 6-(methylthio)purine (XXXIX) is demethylated by the rat to 6-mercaptopurine [205]. This demethylation occurs in the liver micro-somes and is an oxidative process which converts the methyl group to formaldehyde [204, 207]. The 1-methyl derivative of 4-aminopyrazolo[3,4-d] pyrimidine (XLI) is demethylated slowly, but 6-mercapto-9-methylpurine (XLII) not at all [208]. The A -demethylation of puromycin (XLlIl) [209, 210], its aminonucleoside (XLIV) [211], and a number of related compounds, including V-methyladenine and V,V-dimethyladenine, occurs in the liver microsomes of rodents [212]. In the guinea-pig the rate-limiting step in the metabolism of the aminonucleoside appears to be the demethylation of the monomethyl compound, which is the major urinary metabolite [213]. The relationship of lipid solubility to microsomal metabolism [214], and the induction of these demethylases in rats by pre-treatment with various drugs have been studied [215]. 

Studies on the mechanism of action of 6-mercaptopurine are complicated by the fact that its anabolic product, thioinosinic acid, is further metabolized by oxidation to 6-thioxanthylic acid [219] and by methylation to 6-(methylthio)purine ribonucleotide [206, 296]. the effects of which could be even more important than those of thioinosinic acid itself, since the methylthio compound is about 20 times as potent as a feedback inhibitor [289]. 

The pyrazolo[3, 4-d] pyrimidines are substrates for and inhibitors of xanthine oxidase [266, 267]. 4-Hydroxypyrazolo[3,4-d] pyrimidine was first investigated for its ability to protect 6-mercaptopurine and other analogues from oxidation by xanthine oxidase [384], but it also inhibits the oxidation of the natural purines, hypoxanthine, and xanthine. Its profound effect on uric acid metabolism made it an obvious choice for the treatment of gout and its utility in the control of this disease has been demonstrated [385, 386]. 

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. 

Certain derivatives of 6-mercaptopurine, such as 6-(methylthio)purine, 6-mercaptopurine-3-oxide [448a], and 6-mercaptopurine ribonucleoside and its acylated derivatives apparently owe their activity to their in vivo conversion to 6-mercaptopurine [11,13]. It would appear, however, that the 9-alkyl derivatives of 6-mercaptopurine, and its arabinosyl and xylosyl derivatives, are not metabolized-except in the case of the 9-alkyI derivatives, to a limited extent to their 5-glucuronides—and that their mechanism of action is quite different from that of 6-mercaptopurine. 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

The cytostatic drugs administered (indicated by a syringe in the illustration) are often not active themselves but are only converted into the actual active agent in the metabolism. This also applies to the adenine analogue 6-mercaptopurine, which is initially converted to the mononucleotide tIMP (thioinosine monophosphate). Via several intermediate steps, tIMP gives rise to tdGTP, which is incorporated into the DNA and leads to crosslinks and other anomalies in it. The second effective metabolite of 6-mercaptopurine is S-methylated tIMP, an inhibitor of amidophos-phoribosyl transferase (see p. 188). 

Mercaptopurine is well absorbed after oral administration. First pass metabolism in the liver results in 5-37% bioavailability. It is eliminated by xanthine oxidase, thus allopurinol can considerably increase its blood levels and potentiate its effects. 

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