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Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis
Author(s) -
Czaja Albert J.
Publication year - 2020
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.15743
Subject(s) - thiopurine methyltransferase , medicine , azathioprine , efficacy , autoimmune hepatitis , pharmacology , drug , bioavailability , metabolite , hepatitis , disease
Summary Background Thiopurines in combination with glucocorticoids are used as first‐line, second‐line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. Aims To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. Methods English abstracts were identified in PubMed by multiple search terms. Full‐length articles were selected for review, and secondary and tertiary bibliographies were developed. Results Thiopurine methyltransferase activity and 6‐tioguanine (6‐thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre‐treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose‐restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6‐tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. Conclusions The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.