title: Metabolite monitoring to guide thiopurine therapy in systemic autoimmune diseases.
abstract: 6-Thioguanine nucleotide (6-TGN) is the active metabolite of thiopurine drugs azathioprine and 6-mercaptopurine. 6-Methylmercaptopurine (6-MMP) is an inactive and potentially hepatotoxic metabolite. A subgroup of patients (shunters) preferentially produce 6-MMP instead of 6-TGN, therefore displaying thiopurine resistance and risk for hepatotoxicity. Outside inflammatory bowel disease literature, few data exist regarding individualized thiopurine therapy based on metabolite monitoring. This study sought to describe metabolite monitoring in patients receiving weight-based thiopurine for systemic autoimmune diseases. Patients were enrolled using a laboratory database, and data were retrospectively collected. The correlation between the highest thiopurine dose (mg/kg) and the 6-TGN concentration (pmol/8 × 108erythrocytes) was estimated with Pearson's correlation coefficient. Seventy-one patients with various systemic autoimmune conditions were enrolled. The correlation between the thiopurine dose and the 6-TGN level was weak for the overall patient sample (r = 0.201, p = 0.092) and for the subgroup of non-shunters (r = 0.278, p = 0.053). Subjects with 6-MMP levels >5700 pmol/8 × 108erythrocytes had more hepatic cytolysis compared to subjects with 6-MMP <5700, OR = 4.36 (CI 95% 1.18-16.13, p = 0.027). Twenty-two patients (31%) were identified as shunters. Six shunters developed hepatotoxicity, five of which had 6-MMP concentration >5700. Eleven non-shunters had hepatotoxicity, one of which had 6-MMP >5700. Thiopurine metabolite monitoring shows wide variability in 6-TGN levels among patients treated with weight-based thiopurine for systemic autoimmune diseases. Thirty-one percent of the patients in our series fulfilled the shunter definition. Thiopurine metabolite monitoring and dose adjustment to improve maintenance of remission and avoid hepatotoxicity should be studied prospectively.
authors.affiliation: Department of Medicine, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada. aurelie.chapdelaine@umontreal.ca.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Chapdelaine
authors.affiliation: Department of Medicine, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada.|Faculty of Medicine, Université de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mansour
authors.affiliation: Department of Medicine, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada.
authors.forename: Yves
authors.initials: Y
authors.lastname: Troyanov
authors.affiliation: Department of Pharmacy, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada.|Faculty of Pharmacy, Université de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada.
authors.forename: David R
authors.initials: DR
authors.lastname: Williamson
authors.affiliation: Department of Pharmacy, Hôpital du Sacré-Cœur de Montréal, 5400 Gouin Ouest, Montréal, Québec, H4J 1C5, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Doré
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000150:complications / Q000188:drug therapy*; D001379:Azathioprine / Q000378:metabolism / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004342:Drug Hypersensitivity / Q000097:blood* / Q000150:complications / Q000175:diagnosis / Q000453:epidemiology; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007970:Leukopenia; D008297:Male; D015122:Mercaptopurine / Q000097:blood; D008780:Methyltransferases / Q000097:blood; D008875:Middle Aged; D015995:Prevalence; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000097:blood* / Q000150:complications / Q000175:diagnosis / Q000453:epidemiology; D011792:Quebec / Q000453:epidemiology; D012189:Retrospective Studies; D013873:Thionucleotides / Q000097:blood*
chemical_list: D018501:Antirheumatic Agents; D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine
keywords: Allopurinol; Azathioprine; Connective tissue disease; Dose-response relationship; Drug monitoring; Vasculitis