Azathioprine Biotransformation in Young Patients with Inflammatory Bowel Disease: Contribution of Glutathione-S Transferase M1 and A1 Variants

Abstract

The contribution of candidate genetic variants involved in azathioprine biotransformation on azathioprine efficacy and pharmacokinetics in 111 young patients with inflammatory bowel disease was evaluated. Azathioprine doses, metabolites thioguanine-nucleotides (TGN) and methylmercaptopurine-nucleotides (MMPN) and clinical effects were assessed after at least 3 months of therapy. Clinical efficacy was defined as disease activity score below 10. Candidate genetic variants (TPMT rs1142345, rs1800460, rs1800462, GSTA1 rs3957357, GSTM1, and GSTT1 deletion) were determined by polymerase chain reaction (PCR) assays and pyrosequencing. Statistical analysis was performed using linear mixed effects models for the association between the candidate variants and the pharmacological variables (azathioprine doses and metabolites). Azathioprine metabolites were measured in 257 samples (median 2 per patient, inter-quartile range IQR 1-3). Clinical efficacy at the first evaluation available resulted better in ulcerative colitis than in Crohn’s disease patients (88.0% versus 52.5% responders, p = 0.0003, linear mixed effect model, LME). TGN concentration and the ratio TGN/dose at the first evaluation were significantly higher in responder. TPMT rs1142345 variant (4.8% of patients) was associated with increased TGN (LME p = 0.0042), TGN/dose ratio (LME p < 0.0001), decreased azathioprine dose (LME p = 0.0087), and MMPN (LME p = 0.0011). GSTM1 deletion (58.1% of patients) was associated with a 18.5% decrease in TGN/dose ratio and 30% decrease in clinical efficacy. GSTA1 variant (12.8% of patients) showed a trend (p = 0.049, LME) for an association with decreased clinical efficacy; however, no significant effect on azathioprine pharmacokinetics could be detected. In conclusion, GSTs variants are associated with azathioprine efficacy and pharmacokinetics.

Characterization of Cytosolic Glutathione S-Transferases Involved in the Metabolism of the Aromatase Inhibitor, Exemestane

“…The GSTM1 null genotype also has been linked with alterations in drug metabolism and clinical efficacy. For example, the GSTM1 null genotype has been associated with lower efficacy in patients taking azathioprine (AZA) as an immunosuppressant during inflammatory bowel disease (Lucafò et al, 2019). These GST functional variants may therefore contribute to the variability in hepatic EXE metabolism in the population.…”

Personalized Medicine of Monoclonal Antibodies in Inflammatory Bowel Disease: Pharmacogenetics, Therapeutic Drug Monitoring, and Beyond

“…This strategy may also evaluate the risk of disappointing efficacy or toxicities associated with thiopurines, methotrexate, aminosalicylates, and immunosuppressants ( Voskuil et al, 2019 ), both in adults ( Heap et al, 2014 ; Heap et al,2016 ; Kakuta et al, 2018 ; Walker et al, 2019 ) and children ( Lucafò et al, 2019 ). This approach is valuable when TDM protocols require chromatographic methods that can be laborious and need specific expertise as in the case of thiopurines.…”

Combining explainable machine learning, demographic and multi-omic data to inform precision medicine strategies for inflammatory bowel disease

“…The enzyme GST-M1 is involved in the metabolism of azathioprine [ 27 ]. Its expression has been linked to greater azathioprine efficacy [ 28 ] but has also been implicated in the adverse effects and toxicity frequently observed in patients who are either on a high dose or on long term treatment with azathioprine [ 29 ]. Another role of GST-M1 is as a negative regulator of p38 MAPK by physically sequestering ASK-1, a MAPK kinase kinase, which activates p38 MAPK [ 30 ].…”