Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The commonly used immunosuppressive regimen after orthotopic heart transplantation consists of cyclosporine (CsA), azathioprine (AZA), and steroids. Although AZA therapy is generally regarded as unproblematic, its use can be associated with severe side effects, particularly myelosuppression. Since AZA is a prodrug, which must first be metabolized to its active metabolites, AZA therapy, in contrast to CsA therapy, cannot be controlled by measuring blood levels of this drug. Because of the myelosuppressive properties of the AZA metabolites, the 6-thioguanine nucleotides (6-TGN), the white blood cell count is usually monitored in patients on AZA therapy, and AZA is discontinued if neutropenia appears. In a group of 20 consecutive heart recipients, 6-TGN concentrations ranged from < 30 to 2,211 pmol/8 x 10(8) red blood cells (RBCs); levels < or = 450 pmol/8 x 10(8) RBCs were not associated with AZA-induced myelosuppression. Three cases of neutropenia were experienced, two of them with a fatal outcome. One patient died in septicemia owing to total myelosuppression. In this case an excessively high erythrocyte 6-TGN concentration (2,211 pmol/8 x 10(8) RBCs) was associated with a complete deficiency of thiopurine methyltransferase (TPMT), one of the main AZA detoxifying enzymes. The second patient, who had high RBC TPMT activity, developed neutropenia during rehabilitation, and AZA was withdrawn. Coincidentally, in this case the CsA blood level was only 132 g/L, and the RBC 6-TGN level was very low (maximum 46 pmol/8 x 10(8) RBCs). This patient rapidly developed cardiogenic shock with clinical signs of acute rejection and was given a second transplant on an emergency basis, but finally died from rejection of the second graft. Retrospectively, it was determined that neutropenia in this patient was not related to AZA toxicity. A high 6-TGN level (698 pmol/8 x 10(8) RBCs) was also seen in a third patient with mild neutropenia, who required allopurinol, an inhibitor of xanthine oxidase, the other major detoxifying enzyme for AZA. In this patient AZA therapy could be individually adapted by RBC 6-TGN monitoring. Based on our experience, we suggest that RBC 6-TGN monitoring allows for better individualization of treatment with AZA and may help avoid fatal complications.
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PMID:Should 6-thioguanine nucleotides be monitored in heart transplant recipients given azathioprine? 873 60

This review describes the pharmacokinetics of the major drugs used for the treatment of inflammatory bowel disease. This information can be helpful for the selection of a particular agent and offers guidance for effective and well tolerated regimens. The corticosteroids have a short elimination half-life (t1/2beta) of 1.5 to 4 hours, but their biological half-lives are much longer (12 to 36 hours). Most are moderate or high clearance drugs that are hepatically eliminated, primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. Prednisone and budesonide undergo presystemic elimination. Any disease state or comedication affecting CYP3A4 activity should be taken into account when prescribing corticosteroids. Depending on the preparation used, 10 to 50% of an oral or rectal dose of mesalazine is absorbed. Rapid acetylation in the intestinal wall and liver (t1/2beta 0.5 to 2 hours) and transport probably by P-glycoprotein affect mucosal concentrations of mesalazine, which apparently determine clinical response. Any clinical condition influencing the release and topical availability of mesalazine might modify its therapeutic potential. Metronidazole has high (approximately 90%) oral bioavailability, with hepatic elimination characterised by a t1/2beta of 6 to 10 hours and a total clearance of about 4 L/h/kg. Ciprofloxacin is largely excreted unchanged both renally (about 45% of dose) and extrarenally (25%), with a relatively short t1/2beta (3.5 to 7 hours). Thus, renal function affects the systemic availability of ciprofloxacin. Both mercaptopurine and its prodrug azathioprine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolites by the polymorphically expressed thiopurine S-methyltransferase (TPMT) and xanthine oxidase. Patients with low TPMT activity have a higher risk of developing haemopoietic toxicity. Both mercaptopurine and azathioprine have a short t1/2beta (1 to 2 hours), but the t1/2beta of 6-TGN ranges from 3 to 13 days. Therapeutic response seems to be related to 6-TGN concentration. Almost complete bioavailability has been observed after intramuscular and subcutaneous administration of methotrexate, which is predominantly (85%) excreted as unchanged drug with a t1/2beta of up to 50 hours. Thus, renal function is the major determinant for disposition of methotrexate. Cyclosporin is slowly and incompletely absorbed. It is extensively metabolised by CYP3A4/5 in the liver and intestine (median t1/2beta and clearance 7.9 hours and 0.46 L/h/kg, respectively), and inhibitors and inducers of CYP3A4 can modify response and toxicity. Infliximab is predominantly distributed to the vascular compartment and eliminated with a t1/2beta between 10 and 14 days. No accumulation was observed when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum.
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PMID:Pharmacokinetic considerations in the treatment of inflammatory bowel disease. 1170 60

Azathioprine (AZA) is widely used in the treatment of autoimmune inflammatory diseases. AZA is normally rapidly and almost completely converted to 6-mercaptopurine (6-MP) in the liver, which is further metabolized into a variety of pharmacologic active thiopurine metabolites. 6-MP is catabolized by xanthine oxidase (XO) to the inactive metabolite 6-thiouric acid. The authors report the case of a woman with chronic autoimmune pancreatitis unable to form active thiopurine metabolites. The 55-year-old woman presented with weight loss, progressive elevation of liver transaminases, and serum amylase. She was treated with prednisolone 30 mg/day (1 mg/kg) and AZA was increased to 75 mg/day (2.5 mg/kg); this was later increased to 150 mg/day (5 mg/kg). Despite good patient compliance, the active metabolites of AZA, 6-thioguanine nucleotides (6-TGN), and 6-methylmercaptopurine ribonucleotides (6-MMPR) could not be detected in the erythrocytes (RBC). Subsequently, AZA was switched to high-dose 6-MP (2.5 mg/kg) and the XO inhibitor allopurinol was added. After 1 week, this combination led to a high 6-TGN level of 616 pmol/8 x 10(8) RBC and a 6-MMPR level of 1319 pmol/8 x 10(8) RBC. Three weeks after starting treatment, 6-TGN and 6-MMPR even reached toxic levels (1163 pmol/8 x 10(8) RBC and 10015 pmol/8 x 10(8) RBC, respectively) so that 6-MP treatment was discontinued. To elucidate this finding, 6-MP (1.7 mg/kg) was prescribed for 3 days without allopurinol. The woman was not able to form active thiopurine metabolites. According to the authors, this is the first report of a patient unable to form detectable active thiopurine metabolites on AZA and 6-MP therapy despite good patient compliance. High XO activity led to an inability to form detectable levels of active thiopurine metabolites 6-TGN and 6-MMPR. This finding emphasizes the important role of XO in the biotransformation of thiopurines.
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PMID:The role of xanthine oxidase in thiopurine metabolism: a case report. 1804 86

The thiopurine immunomodulators azathioprine and 6-mercaptopurine are integral to the management of inflammatory bowel disease (IBD), particularly as corticosteroid-sparing and maintenance agents; however, up to 50% of patients do not adequately respond to these agents. Advances in pharmacogenomics and an increased understanding of thiopurine metabolism have led to the practice of measuring the thiopurine metabolites 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) to help achieve optimal immunomodulator dosages. Metabolite profiles are also useful for categorizing the reasons for thiopurine treatment failures. A desirable metabolite profile favors 6-TGN production over 6-MMP formation; however, a significant subgroup of IBD patients, perhaps 15%, preferentially metabolizes thiopurines toward the inefficacious and potentially hepatotoxic metabolite 6-MMP. The xanthine oxidase inhibitor allopurinol has been shown recently to advantageously switch thiopurine metabolism toward 6-TGN production in this subgroup of patients, and small studies have shown this switch to be safe and clinically beneficial. This article reviews evidence describing the use of allopurinol to optimize immunomodulator metabolism, provides careful practice guidelines to clinicians considering this strategy, and briefly discusses the potential mechanisms by which this favorable interaction occurs.
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PMID:Use of allopurinol to optimize thiopurine immunomodulator efficacy in inflammatory bowel disease. 2196 Sep 30

A 62-year-old woman with type 1 autoimmune hepatitis (AIH) failed to sustain remission when steroids were withdrawn from a regimen of steroids and azathioprine (AZA). Thiopurine metabolites revealed elevated 6-MMP (6-methyl mercaptopurine) and low 6-TGN (6-thioguanine nucleotide) consistent with AZA-induced hepatotoxicity. Introducing the xanthine oxidase inhibitor allopurinol led to rapid normalization of alanine aminotransferase (ALT) and discontinuation of steroids.
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PMID:Use of a xanthine oxidase inhibitor in autoimmune hepatitis. 2323 20