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Clinical Pharmacology and Therapeutics May 2019Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme...
Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmacologic effects of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).
Topics: Antimetabolites, Antineoplastic; Azathioprine; Dose-Response Relationship, Drug; Drug Dosage Calculations; Humans; Inactivation, Metabolic; Mercaptopurine; Methyltransferases; Pharmacogenetics; Pharmacogenomic Testing; Pyrophosphatases; Thioguanine
PubMed: 30447069
DOI: 10.1002/cpt.1304 -
Xenobiotica; the Fate of Foreign... Jan 2020The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although... (Review)
Review
The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response. variants are a common cause of severe myelotoxicity in Asian populations where the frequency of TPMT deficiency is low. There is increasing evidence that testing for NUDT15 and TPMT deficiency in all populations prior to the start of thiopurine therapy is clinically useful and should be the first step in personalising thiopurine therapy.
Topics: Azathioprine; Drug Hypersensitivity; Erythrocytes; Female; Genotype; Humans; Male; Mercaptopurine; Methyltransferases; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purine-Pyrimidine Metabolism, Inborn Errors; Purines
PubMed: 31682552
DOI: 10.1080/00498254.2019.1688424 -
Journal of Crohn's & Colitis Jul 2023Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND AIMS
Scepticism about the efficacy of thiopurines for ulcerative colitis [UC] is rising. This study aimed to evaluate mercaptopurine treatment for UC.
METHODS
In this prospective, randomized, double-blind, placebo-controlled trial, patients with active UC, despite treatment with 5-aminosalicylates [5-ASA], were randomized for therapeutic drug monitoring [TDM]-guided mercaptopurine treatment or placebo for 52 weeks. Corticosteroids were given in the first 8 weeks and 5-ASA was continued. Proactive metabolite-based mercaptopurine and placebo dose adjustments were applied from week 6 onwards by unblinded clinicians. The primary endpoint was corticosteroid-free clinical remission and endoscopic improvement [total Mayo score ≤2 points and no item >1] at week 52 in an intention-to-treat analysis.
RESULTS
Between December 2016 and April 2021, 70 patients were screened and 59 were randomized at six centres. In the mercaptopurine group, 16/29 [55.2%] patients completed the 52-week study, compared to 13/30 [43.3%] on placebo. The primary endpoint was achieved by 14/29 [48.3%] patients on mercaptopurine and 3/30 [10%] receiving placebo (Δ = 38.3%, 95% confidence interval [CI] 17.1-59.4, p = 0.002). Adverse events occurred more frequently with mercaptopurine [808.8 per 100 patient-years] compared to placebo [501.4 per 100 patient-years]. Five serious adverse events occurred, four on mercaptopurine and one on placebo. TDM-based dose adjustments were executed in 22/29 [75.9%] patients, leading to lower mercaptopurine doses at week 52 compared to baseline.
CONCLUSIONS
Optimized mercaptopurine treatment was superior to placebo in achieving clinical, endoscopic and histological outcomes at 1 year following corticosteroid induction treatment in UC patients. More adverse events occurred in the mercaptopurine group.
Topics: Humans; Colitis, Ulcerative; Mercaptopurine; Prospective Studies; Mesalamine; Remission Induction
PubMed: 36847130
DOI: 10.1093/ecco-jcc/jjad022 -
[Rinsho Ketsueki] the Japanese Journal... 2022Therapeutic response and drug-induced toxicity have been reported to be associated with genetic variants of drug-metabolizing enzymes and transporters. Recently, new... (Review)
Review
Therapeutic response and drug-induced toxicity have been reported to be associated with genetic variants of drug-metabolizing enzymes and transporters. Recently, new causative variants associated with drug response have been reported by genome-wide association studies (GWASs). Additionally, therapeutic response has been predicted using a model of multiple single-nucleotide polymorphisms. In acute lymphoblastic leukemia (ALL), the genetic variants of NUDT15 associated with therapeutic response to 6-mercaptopurine (6-MP) have been reported by GWASs, and the frequency of NUDT15 variants was higher in Asians. Then, several reports on NUDT15 genetic variants associated with 6-MP-induced toxicities and the tolerable doses and outcomes of 6-MP therapy for ALL have been published in Asian countries. The drugs used in treating hematological malignancies have reported new genetic variants associated with its therapeutic response. However, the association between these genetic variants has not been validated in other populations. Here, we reviewed recent reports on the association between the genetic variants and response to drugs used in treating hematological malignancies, such as 6-MP, cytarabine, methotrexate, and vincristine.
Topics: Humans; Pharmacogenetics; Pyrophosphatases; Genome-Wide Association Study; Antimetabolites, Antineoplastic; Mercaptopurine; Hematologic Neoplasms
PubMed: 36351640
DOI: 10.11406/rinketsu.63.1353 -
Gastroenterology Clinics of North... Dec 2020This article reviews nonbiologic immunosuppressive agents in the induction and maintenance of remission of ulcerative colitis. Based on meta-analyses and North American... (Review)
Review
This article reviews nonbiologic immunosuppressive agents in the induction and maintenance of remission of ulcerative colitis. Based on meta-analyses and North American guidelines, azathioprine, mercaptopurine, and methotrexate monotherapy are not recommended for induction therapy. Thiopurines are recommended in combination with infliximab. Tofacitinib has been shown to be an effective induction agent. Cyclosporine or tacrolimus are calcineurin inhibitors that can be used as induction therapy. Thiopurine monotherapy is suggested or recommended as maintenance therapy for patients who have achieved steroid-induced remission. Methotrexate monotherapy is not recommended. Tofacitinib has been shown to be an effective maintenance agent in moderate to severe disease.
Topics: Azathioprine; Colitis, Ulcerative; Contraindications, Drug; Glucocorticoids; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Mercaptopurine; Meta-Analysis as Topic; Methotrexate; Piperidines; Pyrimidines; Remission Induction
PubMed: 33121692
DOI: 10.1016/j.gtc.2020.07.003 -
Biochemical and Biophysical Research... Jan 2023Skin is the biggest organ of the human body, which easily gets irritated by exposure to the sun. Skin photoaging and acute photodamage are caused by intense UV-B...
Skin is the biggest organ of the human body, which easily gets irritated by exposure to the sun. Skin photoaging and acute photodamage are caused by intense UV-B radiation. Therefore, it is imperative to find new compounds to prevent skin damage and aging. Mercaptopurine is an immunologic agent commonly used for treating Acute lymphoblastic leukemia and inflammatory bowel disease. The beneficial effects of mercaptopurine on the skin have not been reported, and its intrinsic mechanism of action is unclear. Therefore, this study was to explore mercaptopurine when exposed to UV-B radiation in HacaT cells and C57BL6 mice aging and damage effects. The model of in vivo UV-B-induced skin damage and skin photoaging was established, and the impact of mercaptopurine on cell and animal skin was studied. The study found that mercaptopurine, on the one hand, inhibits cellular and animal senescence. On the other, it inhibits the expression of mitogen-activated protein kinase (MAPK) and the nuclear factor κB (NF-κB), which are important signaling molecules in the early UV-B reaction signaling pathway. In addition, mercaptopurine downregulates matrix metalloproteinase expression, increases collagen fiber content, and facilitates collagen synthesis. Treatment with mercaptopurine also inhibits the expression of inflammatory factors and reduces inflammatory cell infiltration of the skin. In conclusion, our study elucidates mercaptopurine's anti-photoaging and anti-inflammatory activity in cellular and animal models.
Topics: Animals; Humans; Mice; Mercaptopurine; Mice, Inbred C57BL; Skin; Anti-Inflammatory Agents; Skin Aging; Aging; Collagen; Ultraviolet Rays; Fibroblasts
PubMed: 36442232
DOI: 10.1016/j.bbrc.2022.11.035 -
Breastfeeding Medicine : the Official... Apr 2020A 35-year-old pregnant woman visited our outpatient clinical questioning the safety of once daily 50 mg mercaptopurine (MP) during pregnancy and lactation, which was...
A 35-year-old pregnant woman visited our outpatient clinical questioning the safety of once daily 50 mg mercaptopurine (MP) during pregnancy and lactation, which was successfully treating her Crohn's disease. We measured MP and its metabolites in plasma and breast milk and found after 4 hours of intake of MP, no MP or its metabolites in breast milk. We concluded that 4 hours after intake of MP, no exposure of the suckling infant to MP and its metabolites was found while being breastfed.
Topics: Adult; Breast Feeding; Crohn Disease; Female; Humans; Infant; Lactation; Mercaptopurine; Milk, Human; Pregnancy
PubMed: 31414890
DOI: 10.1089/bfm.2019.0101 -
Cell Reports. Medicine Aug 2023Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role...
Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.
Topics: Animals; Mice; Mercaptopurine; Azathioprine; Immunosuppressive Agents; Biological Availability; Inflammatory Bowel Diseases; Colitis; Bacteria
PubMed: 37586320
DOI: 10.1016/j.xcrm.2023.101153 -
Interdisciplinary Sciences,... Jun 2016Thiopurine methyltransferase (TPMT) is a cytoplasmic transmethylase present in both prokaryotes and eukaryotes. In humans, it shows its presence in almost all of the... (Review)
Review
Thiopurine methyltransferase (TPMT) is a cytoplasmic transmethylase present in both prokaryotes and eukaryotes. In humans, it shows its presence in almost all of the tissues, predominantly in liver and kidney. TPMT is one of the important metabolic enzymes of phase II metabolic pathway and catalyzes methylation of thiopurine drugs such as azathioprine, 6-thioguanine and 6-mercaptopurine, which are used to treat patients with neoplasia and autoimmune disease as well as transplant recipients. In this sense, TPMT acts as shield against toxic effect of these drugs. Pharmacogenomic studies revealed that genetic polymorphism in TPMT is responsible for variable and, in some cases, adverse drug reaction. Those human groups who carry variants of TPMT (i.e., [Formula: see text], [Formula: see text], [Formula: see text]) are at high risk, because they are unable to metabolize thiopurine drugs thus becoming a weakness of patients against these drugs. Keeping in the mind the importance of TPMT, this review discusses the existence and distribution of various TPMT variants throughout different ethnic groups and risk of adverse drug reactions to them, and how they can avoid this risk of side effects. The review also highlighted factors responsible for variable reactions of TPMT, how this TPMT polymorphism can be considered in drug designing process to avoid toxic effects, designing precautions against them and more importantly designing personalized medicine.
Topics: Animals; Azathioprine; Drug Design; Humans; Mercaptopurine; Methyltransferases; Polymorphism, Genetic; Thioguanine
PubMed: 26297310
DOI: 10.1007/s12539-015-0111-1 -
BMJ Case Reports Feb 2024Sweet's syndrome is an acute febrile neutrophilic dermatosis. Drug-induced Sweet's syndrome typically occurs soon after drug administration, with rapid resolution of...
Sweet's syndrome is an acute febrile neutrophilic dermatosis. Drug-induced Sweet's syndrome typically occurs soon after drug administration, with rapid resolution of symptoms with cessation of the offending agent. We report a man in his early 40s who presented with fever and widespread erythematous rash on a background of recently diagnosed mild stricturing ileal Crohn's disease. He was commenced on 6-mercaptopurine 12 days before presentation. Skin biopsy demonstrated diffuse infiltration of neutrophils in the upper dermis, dermal oedema, eosinophils and fibrin deposition. Symptoms rapidly improved with cessation of 6-mercaptopurine without requiring systemic corticosteroids.
Topics: Male; Humans; Sweet Syndrome; Mercaptopurine; Skin; Adrenal Cortex Hormones; Crohn Disease
PubMed: 38417937
DOI: 10.1136/bcr-2023-259278