[Not Available]

Area of Science:

• Pharmacogenomics
• Immunosuppression
• Drug Metabolism

Context:

• Azathioprine, 6-mercaptopurine, and 6-thioguanine are crucial immunosuppressive drugs used in transplantation, autoimmune diseases, and inflammatory bowel disease (IBD).
• Their efficacy and safety are influenced by genetic variations in thiopurine methyl transferase (TPMT), an enzyme critical for their metabolism.
• Optimal therapeutic drug monitoring (TDM) strategies for active metabolites, like 6-thioguanine nucleotides (6-TGN), are still debated, especially in IBD.

Purpose:

• To review the metabolism of thiopurine drugs and the role of TPMT.
• To discuss the clinical utility of therapeutic drug monitoring of 6-TGN concentrations in IBD.
• To highlight the association between metabolite concentrations and adverse events, guiding personalized dosing.

Summary:

• Thiopurine drugs are metabolized by TPMT, with activity varying due to genetic polymorphisms.
• Monitoring intra-erythrocyte 6-TGN concentrations is proposed for adherence, therapeutic failure, and managing patients with altered TPMT activity or drug interactions.
• Elevated 6-TGN and methylated metabolites correlate with bone marrow and hepatic toxicity.

Impact:

• Pre-treatment screening of TPMT activity or genotype in IBD patients can enable adapted dosing.
• This personalized approach aims to mitigate severe side effects like myelosuppression and hepatotoxicity.
• Optimizing thiopurine therapy through pharmacogenetic testing can improve patient outcomes and treatment adherence.