Deletion of Glutathione-S-Transferase M1 Reduces Azathioprine Metabolite Concentrations in Young Patients With Inflammatory Bowel Disease

Abstract

This study describes the effect of candidate genetic polymorphisms in TPMT, ITPA, and GST-M1 on azathioprine pharmacokinetics in IBD patients, showing, for the first time, relevant effects of GST-M1 genotype on azathioprine metabolites concentration.

Update on Thiopurine Pharmacogenetics in Inflammatory Bowel Disease

“…Two recent studies by Stocco et al [22,23] provide evidence to support the idea that GST polymorphisms - [52] Ansari et al Update on thiopurine pharmacogenetics in inflammatory bowel disease Review may play a clinically significant role in determining azathioprine response and toxicity. In their first study [22], 55 azathioprine tolerators and 15 nontolerators, of known TPMT status, were genotyped for specific loss-of-function polymorphisms in GST-M1, P1 and T1.…”

“…In the second study, Stocco et al [23] evaluated the impact of the GST-M1 gene deletion on azathioprine metabolism in 75 patients with IBD who had tolerated azathioprine for >3 months. Patients with the GST-M1 deletion tolerated higher doses of azathioprine (mean dose: 2.1 mg/kg per day vs 1.8 mg/kg per day, p = 0.022) and produced fewer 6-TGNs (mean concentration: 164 pmol/8 × 10 8 RBC vs 252 pmol/8 × 10 8 RBC, p = 0.003), compared with patients with a wild-type GST-M1 genotype [23] (Table 1). These associations were independent of TPMT status.…”

Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia

“…The details of the measurement method have been described previously . For each individual patient, the ratio of 6‐MeMPN to 6‐TGN and the ratio of the 6‐TGN to 6‐MP dose was calculated to analyse the patient's pharmacological phenotype …”

Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease

“…Moreover, among the 55 patients who did not develop adverse effects, there was a significant underrepresentation of the GST‐M1 null genotype among patients who displayed lymphopenia as compared with those that did not display this effect of azathioprine (OR, 0.15; 95% CI, 0.013–1.08; P = 0.032) . In an evaluation of the association between genotype of GST‐M1 and thiopurine metabolites in 75 young IBD patients treated with AZA, GST‐M1 deletion was associated with a lower TGN/dose ratio ( P = 0.0030), higher AZA dose requirement ( P = 0.022) and reduced response to therapy ( P = 0.0022) …”