title: Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease.
abstract: The thiopurine drugs azathioprine and 6-mercaptopurine (6-MP) are well-established in the treatment of inflammatory bowel disease (IBD). However, there is a wide inter- and intra-patient variation in the concentrations of active and toxic metabolites due to their complex metabolism and genetic polymorphisms in metabolizing enzymes. Serious drug toxicity leads to cessation of therapy in 9-25% of patients, and there is failure to achieve efficacy in approximately 15% of cases. Advances in the understanding of thiopurine drug metabolism have led to new genetic and metabolite tests to help clinicians optimize thiopurine use. Thiopurine methyltransferase (TPMT) enzyme activity can predict life-threatening myelotoxicity in the one in 300 patients who are TPMT-deficient. However, myelotoxicity can also occur in the presence of normal TPMT activity so blood count monitoring should remain standard practice. TPMT testing may also aid in dose individualization. 6-Thioguanine nucleotides (6-TGN) are thought to be the predominant active metabolites of the thiopurines. 6-thioguanine nucleotide concentration is correlated with bone marrow toxicity and may also correlate with efficacy in IBD. Measurement of 6-TGN and 6-methylmercaptopurine (6-MMP) concentration is most useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression. The ratio of these metabolites can help distinguish non-compliance, under-dosing, thiopurine-resistant and thiopurine-refractory disease. Some of these investigations are entering routine clinical practice but more research is required to determine their optimal use in patients with IBD.
authors.affiliation: Department of Gastroenterology, Christchurch Hospital, Christchurch School of Medicine and Health Sciences, New Zealand. Richard.Gearry@cdhb.govt.nz
authors.forename: Richard B
authors.initials: RB
authors.lastname: Gearry
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001379:Azathioprine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D004912:Erythrocytes / Q000378:metabolism; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015122:Mercaptopurine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism* / Q000627:therapeutic use*; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics*; D011110:Polymorphism, Genetic; D011755:Pyrophosphatases / Q000172:deficiency; D013873:Thionucleotides / Q000378:metabolism; D000097630:Inosine Triphosphatase
chemical_list: D000964:Antimetabolites, Antineoplastic; D001379:Azathioprine; D006150:Guanine Nucleotides; D015122:Mercaptopurine; D008780:Methyltransferases; D011755:Pyrophosphatases; D013873:Thionucleotides; D000097630:Inosine Triphosphatase; C003964:6-thioguanylic acid; C010240:6-methylthiopurine; C022745:thiopurine methyltransferase