Hepatic. Degradation primarily by xanthine oxidase. The catabolism of mercaptopurine and its metabolites is complex. In humans, after oral administration of <sup>35</sup>S-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. The methylthiopurines yield appreciable amounts of inorganic sulfate.
After oral administration of 35(S)-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines.
Mercaptopurine is metabolized via 2 major pathways. Mercaptopurine is rapidly and extensively oxidized to 6-thiouric acid in the liver by the enzyme xanthine oxidase. Because xanthine oxidase is inhibited by allopurinol, concomitant use of this drug decreases the metabolism of mercaptopurine and its active metabolites and leads to toxicity. If allopurinol and mercaptopurine are used concomitantly, the dosage of mercaptopurine must be reduced to avoid toxicity. Another major catabolic pathway is thiol methylation of mercaptopurine to form the inactive metabolite methyl-6-MP. This reaction is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT). Variability in TPMT activity in patients because of a genetic polymorphism in the TPMT gene causes interindividual differences in the metabolism of mercaptopurine and resulting systemic exposure to the drug and its active metabolites. Dethiolation can also occur, with large portions of the sulfur being excreted as inorganic sulfate.
... In this study, we investigated the in vitro metabolism of 6-mercaptopurine (6MP) to 6-thiouric acid (6TUA) in pooled human liver cytosol. We discovered that 6MP is metabolized to 6TUA through sequential metabolism via the 6-thioxanthine (6TX) intermediate. The role of human AO and XO in the metabolism of 6MP was established using the specific inhibitors raloxifene and febuxostat. Both AO and XO were involved in the metabolism of the 6TX intermediate, whereas only XO was responsible for the conversion of 6TX to 6TUA. These findings were further confirmed using purified human AO and Escherichia coli lysate containing expressed recombinant human XO. Xanthine dehydrogenase (XDH), which belongs to the family of xanthine oxidoreductases and preferentially reduces nicotinamide adenine dinucleotide (NAD(+)), was shown to contribute to the overall production of the 6TX intermediate as well as the final product 6TUA in the presence of NAD(+) in human liver cytosol. In conclusion, we present evidence that three enzymes, AO, XO, and XDH, contribute to the production of 6TX intermediate, whereas only XO and XDH are involved in the conversion of 6TX to 6TUA in pooled HLC.
来源:Hazardous Substances Data Bank (HSDB)
代谢
硫代嘌呤抗代谢物，6-巯基嘌呤（6-MP）和6-硫鸟嘌呤（6-TG）是无效的前药，需要细胞内代谢才能激活为细胞毒性代谢物。硫代嘌呤甲基转移酶（TPMT）是这一过程中最重要的酶之一，它将6-MP和6-TG代谢为不同的甲基化代谢物，包括甲基巯基肌苷一磷酸（meTIMP）和甲基巯基鸟苷一磷酸（meTGMP），分别具有不同的建议药理和细胞毒性特性。虽然meTIMP是脱氧核糖合成（DNPS）的强效抑制剂，显著增加了6-MP的细胞毒性，但meTGMP对6-TG的影响不大，6-TG的细胞毒性似乎更多依赖于硫鸟嘌呤核苷酸（TGNs）并入DNA，而不是抑制DNPS。为了研究TPMT在代谢中的作用，从而研究6-MP和6-TG的细胞毒性作用，我们使用特制的小干扰RNA（siRNA）在人MOLT4白血病细胞中敲低了编码TPMT酶的基因表达。RNA、蛋白质和酶功能水平上证实了敲低的效果。通过annexin V和碘化丙啶染色以及FACS分析确定了凋亡。结果显示，与转染非靶向siRNA的细胞相比，经TPMT靶向siRNA处理的MOLT4细胞对1 uM 6-TG的敏感性增加了34%，而细胞对6-MP的敏感性并未受到TPMT基因下调的显著影响。这种酶TPMT对两种硫代嘌呤细胞毒性的不同贡献可能是由于它在形成meTIMP，即6-MP的细胞毒性甲基化代谢物中的作用，而在6-TG的情况下，TPMT的甲基化实质上使药物失活。
The thiopurine antimetabolites, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are inactive pro-drugs that require intracellular metabolism for activation to cytotoxic metabolites. Thiopurine methyltransferase (TPMT) is one of the most important enzymes in this process metabolizing both 6-MP and 6-TG to different methylated metabolites including methylthioinosine monophosphate (meTIMP) and methylthioguanosine monophosphate (meTGMP), respectively, with different suggested pharmacological and cytotoxic properties. While meTIMP is a potent inhibitor of de novo purine synthesis (DNPS) and significantly contributes to the cytotoxic effects of 6-MP, meTGMP, does not add much to the effects of 6-TG, and the cytotoxicity of 6-TG seems to be more dependent on incorporation of thioguanine nucleotides (TGNs) into DNA rather than inhibition of DNPS. In order to investigate the role of TPMT in metabolism and thus, cytotoxic effects of 6-MP and 6-TG, we knocked down the expression of the gene encoding the TPMT enzyme using specifically designed small interference RNA (siRNA) in human MOLT4 leukemia cells. The knock-down was confirmed at RNA, protein, and enzyme function levels. Apoptosis was determined using annexin V and propidium iodide staining and FACS analysis. The results showed a 34% increase in sensitivity of MOLT4 cells to 1 uM 6-TG after treatment with TPMT-targeting siRNA, as compared to cells transfected with non-targeting siRNA, while the sensitivity of the cells toward 6-MP was not affected significantly by down-regulation of the TPMT gene. This differential contribution of the enzyme TPMT to the cytotoxicity of the two thiopurines is probably due to its role in formation of the meTIMP, the cytotoxic methylated metabolite of 6-MP, while in case of 6-TG methylation by TPMT substantially deactivates the drug.
IDENTIFICATION AND USE: Mercaptopurine is an antineoplastic agent. It is indicated for maintenance therapy of acute lymphatic (lymphocytic, lymphoblastic) leukemia as part of a combination regimen. It may have potential benefit in treating other autoimmune conditions (eg, unresponsive ulcerative colitis) as well. Veterinary uses of mercaptopurine have included adjunctive therapy of lymphosarcoma, acute leukemias, and severe rheumatoid arthritis. HUMAN EXPOSURE AND TOXICITY: Signs and symptoms of overdosage may be immediate (anorexia, nausea, vomiting, and diarrhea); or delayed (myelosuppression, liver dysfunction, and gastroenteritis). Dialysis cannot be expected to clear mercaptopurine. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of mercaptopurine into active metabolites with long persistence. Hepatosplenic T-cell lymphoma, a rare, aggressive, usually fatal type of T-cell lymphoma, has been reported during postmarketing experience mainly in adolescents and young adults with Crohn's disease or ulcerative colitis who received treatment with thiopurine analogs (mercaptopurine or azathioprine) and/or tumor necrosis factor (TNF) blocking agents. Although most of the reported cases occurred in patients who had received a combination of immunosuppressive agents, including TNF blocking agents and thiopurine analogs (mercaptopurine or azathioprine), cases have been reported in patients receiving mercaptopurine or azathioprine alone. Hepatotoxicity manifested by rapid onset of jaundice, cholestasis, ascites, hepatic encephalopathy, and/or elevated hepatic enzyme concentrations, usually associated with hepatic necrosis and severe fibrosis, may occur in patients receiving mercaptopurine; deaths from hepatic necrosis have occurred. In some cases, hepatotoxicity has been associated with anorexia and diarrhea. Hepatic function must be carefully monitored in patients receiving mercaptopurine. Although hepatic injury can occur at any dosage, the incidence appears to increase when dosage exceeds 2.5 mg/kg daily. The most consistent dose-dependent toxicity of mercaptopurine is myelosuppression manifested by anemia, leukopenia, thrombocytopenia, or any combination of these effects. These findings also may reflect progression of disease. Life-threatening infection and bleeding have occurred in patients with mercaptopurine-induced granulocytopenia and thrombocytopenia, respectively. Increases in chromosomal aberrations were found in human peripheral lymphocytes exposed in vitro. ANIMAL STUDIES: After a single lethal dose of mercaptopurine, the majority of rats survive 2 - 3 days, and deaths do not occur in mice until at least 5 days after injection. In rats, early deaths are due to lung damage, a toxic effect not seen in other species such as mouse, cat or dog. ln rats and mice, the predominant toxicity of 6-MP is damage to the bone-marrow and intestinal epithelium and hepatic necrosis. Major toxic symptoms in dogs were marked damage to the small intestinal mucosa and bone-marrow depletion. Biochemical evidence of liver damage was present, and jaundice was apparent in treated animals, although livers had only relatively insignificant microscopic foci of necrosis. Doses of 20, 10 or 5 mg/kg bw mercaptopurine plus the same doses of 6-methylmercaptopurine riboside were reported to increase the incidence of Iymphoreticular tumors in mice. No such effect was seen in rats given 6 or 3 mg/kg bw of each drug. Female mice were treated subcutaneously with 3 mg/kg bw 6-mercaptopurine daily, starting 3 days before mating with untreated males and up through day 18 of pregnancy. Many of the surviving female offspring, although they had normal body weight, development and general appearance, were either sterile or, if they became pregnant, had smaller litters and more dead fetuses as compared with controls. Histological study of the ovaries of offspring exposed to 6-mercaptopurine in utero revealed that there were few oocytes and ovarian follicles; many ovaries were completely devoid of oocytes. Mercaptopurine induced apoptotic cell death in neural cells in the rat fetal brain. Long-term mercaptopurine treatment in male mice did not impair sperm production and sperm morphology. However, a significantly high rate of embryonic resorption indicated occult sperm damage. Mercaptopurine produced dominant lethal effects in vivo in the premeiotic and early meiotic germ cells of male mice and an increase in the number of micronuclei in mouse bone marrow. Chromosomal aberrations were observed in the bone-marrow cells of rats and Chinese hamsters following ip administration of 6-mercaptopurine and in mice after oral or parenteral administration. Mercaptopurine was mutagenic without metabolic activation in Salmonella typhimurium tester strains his G46 and TA 1535.
Mercaptopurine has been associated with several forms of hepatotoxicity. Patients receiving mercaptopurine for leukemia often have transient and asymptomatic rises in serum aminotransferase or alkaline phosphatase levels and a proportion of these patients develop jaundice, particularly when it is given in high doses. In case series of patients with autoimmune diseases (such as inflammatory bowel disease) treated with mercaptopurine, up to 30% developed serum aminotransferase elevations and these can be persistent as long as therapy is continued, resolving either with dose reduction or discontinuation. Liver biopsy usually demonstrates steatosis and centrolobular injury with scant inflammation.
Mercaptopurine can also lead to a distinctive acute, clinically apparent liver injury that usually presents with fatigue and jaundice and a cholestatic or mixed pattern of serum enzyme elevations 1 to 6 months after starting therapy, but sometimes later, particularly following an increase in dose. Serum enzyme levels are often not very high, certainly not in the range that occurs with acute viral hepatiits. Rash, fever and eosinophilia are uncommon and autoantibodies are generally not found. Liver biopsy typically shows a mixed hepatocellular-cholestatic injury with cholestasis, focal hepatocellular necrosis, bile duct injury and variable amounts of inflammation. The injury is idiosyncratic and similar to the cholestatic hepatitis associated with azathioprine. The liver injury usually resolves upon stopping, but prolonged cholestasis has been reported and some cases have been fatal. In large case series and registries, mercaptopurine usually ranks among the top 20 causes of drug induced liver injury, and if combined with cases due to azathioprine [a prodrug of mercaptopurine] would rank among the top 10 more frequent causes.
Chronic therapy with mercaptopurine and other thiopurines can lead to nodular regeneration and symptomatic portal hypertension. This chronic hepatotoxicity typically presents with fatigue and signs and symptoms of portal hypertension (ascites, varices), with mild liver enzyme abnormalities and minimal jaundice arising 6 months to many years after starting mercaptopurine. Liver biopsy shows nodular regenerative hyperplasia without significant fibrosis and varying amounts of sinusoidal dilation and central vein injury. This syndrome can progress to hepatic failure, particularly if mercaptopurine is continued, but gradual improvement on stopping therapy is typical. Rarely, the onset of this syndrome can be acute with abdominal pain and ascites in which situation liver biopsy usually shows sinusoidal dilation, central congestion and injury to sinusoidal endothelial cells suggestive of veno-occlusive disease, which is currently referred to as sinusoidal obstructive syndrome. Typically, serum aminotransferase levels and alkaline phosphatase levels are minimally elevated, even in the presence of hyperbilirubinemia and other manifestations of hepatic dysfunction and portal hypertension. Many cases present initially with unexplained thrombocytopenia, and progressive decreases in platelet counts may be the most sensitive marker for the development of the non-cirrhotic portal hypertension.
Finally long-term therapy with mercaptopurine and other thiopurines has been implicated in leading to the development of malignancies, including hepatocellular carcinoma (HCC) and hepatosplenic T cell lymphoma (HSTCL). Both of these complications are rare but have been reported in several dozen case reports and small case series. In neither instance, has the role of thiopurine therapy in causing the malignacies been proven, and similar cases have been described in patients with autoimmune conditions or after solid organ transplantation who have not received thiopurines. Hepatocellular carcinoma typically arises after years of azathioprine or mercaptopurine therapy and in the absence of accompanying liver disease (although sometimes with focal hepatic glycogenosis). The HCC is most frequently found on an imaging study done of an unrelated condition. The prognosis is more favorable than that of HCC associated with cirrhosis. Hepatosplenic T cell lymphoma has been reported largely among young men with inflammatory bowel disease and long term immunosuppression with a thiopurine with or without anti-tumor necrosis factor therapy. The typical presentation is with fatigue, fever, hepatosplenomegaly and pancytopenia. The diagnosis is made by bone marrow or liver biopsy showing marked infiltration with malignant T cells. HSTCL is poorly responsive to antineoplastic therapy and has a high mortality rate.
Likelihood score: A (well known cause of clinically apparent liver injury).
Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown.
来源:DrugBank
吸收、分配和排泄
分布容积
分布容积超过了总体水容积。
The volume of distribution exceeded that of the total body water.
来源:DrugBank
吸收、分配和排泄
/MILK/ 目前尚不清楚巯嘌呤是否分布到乳汁中。
/MILK/ It is not known whether mercaptopurine is distributed into milk.
Mercaptopurine and its metabolites are distributed throughout total body water. The volume of distribution of mercaptopurine usually exceeds total body water content. Although the drug reportedly crosses the blood-brain barrier, CSF concentrations are not sufficient for the treatment of meningeal leukemia.
Mercaptopurine is excreted in urine as unchanged drug and metabolites. In one study in adults with normal renal function, about 11% of an oral dose was recovered in the urine within 6 hours.
[EN] TREATMENT OR PROPHYLAXIS OF PROLIFERATIVE CONDITIONS<br/>[FR] TRAITEMENT OU PROPHYLAXIE D'ÉTATS PROLIFÉRATIFS
申请人：UNIV DUNDEE
公开号：WO2010125350A1
公开（公告）日：2010-11-04
The invention relates to novel compounds for use in the treatment or prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express cytochrome P450 1B1 (CYP1B1) and allelic variants thereof. The invention also provides pharmaceutical compositions comprising one or more such compounds for use in medical therapy, for example in the treatment of prophylaxis of cancers or other proliferative conditions, as well as methods for treating cancers or other conditions in human or non-human animal patients. The invention also provides methods for identifying novel compounds for use in the treatment of prophylaxis of cancers and other proliferative conditions that are for example characterized by cells that express CYP1 B1 and allelic variants thereof. The invention also provides a method for determining the efficacy of a compound of the invention in treating cancer.
Detoxication of Sulfur Half-Mustards by Nucleophilic Scavengers: Robust Activity of Thiopurines
作者：Jinyun Liu、K. Leslie Powell、Howard D. Thames、Michael C. MacLeod
DOI：10.1021/tx900190j
日期：2010.3.15
Sulfur mustard and monofunctional analogues (half-mustards, 2-[chloroethyl] alkyl sulfides) react as electrophiles, damaging cellular macromolecules, and thus are potentially subject to scavenging by nucleophilic agents. We have determined rate constants for the reaction of four purine derivatives that contain nucleophilic thiol moieties with several sulfur-half-mustards. Three of these compounds, 2,6-dithiopurine
自第一次世界大战以来，硫芥（双（2-氯乙基）硫化物）一直用于化学战，是众所周知的剧毒起泡剂。在长期低水平暴露后，它被认为是一种致癌物质，并且已知会在 DNA 中形成链间交联。由于易于合成，硫和氮芥作为恐怖分子的潜在化学威胁剂目前受到关注。硫芥和单功能类似物（半芥末，2-[氯乙基] 烷基硫化物）作为亲电试剂反应，破坏细胞大分子，因此可能会被亲核试剂清除。我们已经确定了四种含有亲核硫醇部分的嘌呤衍生物与几种半硫芥的反应速率常数。这些化合物中的三种，2,6-二硫嘌呤、2,6-二硫脲酸、和 9-methyl-6-mercaptopurine，与亲电子芥子化合物表现出容易的反应。在接近中性的 pH 值下，这些硫嘌呤是芥末亲电试剂的亲核清除剂，比其他低分子量硫醇（如N-乙酰半胱氨酸和谷胱甘肽。通过数值积分技术计算的进展曲线表明，等摩尔浓度的硫嘌呤显着减少了对表锍离子的总体暴露，这是硫芥子气溶解在水溶液中时产生的主要反应性亲电子试剂。
8-arylalkyl- and
申请人：Boehringer Ingelheim Pharmaceuticals, Inc.
公开号：US05705499A1
公开（公告）日：1998-01-06
Disclosed are novel 8-arylalkyl-5,11-dihydro-6H-dipyrido\x9b3,2-b:2',3'-e!\x9b1,4!diazepines. These are useful in the treatment of HIV-1 infection.
[EN] PYRROLOTRIAZINONE DERIVATIVES AS PI3K INHIBITORS<br/>[FR] DÉRIVÉS DE PYRROLOTRIAZINONE EN TANT QU'INHIBITEURS DE PI3K
申请人：ALMIRALL SA
公开号：WO2012146666A1
公开（公告）日：2012-11-01
New pyrrolotriazinone derivatives having the chemical structure of formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of Phosphoinositide 3-Kinases (PI3Ks).
