Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

Abstract

Background and AimA lower dose requirement and higher toxicity of thiopurine is reported in Asian patients with inflammatory bowel disease (IBD) as compared with Caucasian patients. These reports are based on thiopurine methyltransferase measurement studies rather than metabolite estimation.We studied the utility of thiopurine metabolite estimation in Indian patients with IBD and compared dose and toxicity with Asian and Caucasian patients.MethodsIn this prospective study, 6‐thioguanine nucleotide (6‐TGN) and 6‐methylmercaptopurine levels were determined by HPLC in 76 IBD patients treated with thiopurines. The levels were correlated with dose, disease activity, and toxicity. The dose‐related metabolite levels and toxicity were compared with Caucasian and Asian patients reported in literature.ResultsOf the 76 patients (32 women, mean age: 35.9 [SD: 14.54] years, 36 Crohn's disease and 40 ulcerative colitis), 1 non‐compliant patient had undetectable level of metabolites. Of the 75 patients, 21(28%) had therapeutic level of 6‐TGN, 37(49%) had subtherapeutic level and 17(23%) had supratherapeutic level. The 6‐methylmercaptopurine levels ranged up to 4971 pmol/8 × 108 red blood cells. Six (8%) patients showed toxicity. Thiopurine dose was optimized in 20 (26.31%) patients. Dose‐based metabolite levels were comparable to Asian and Caucasian patients. The toxicity (8%) observed in our patients was less than that reported (12–39%).ConclusionHalf of the patients in this study had low and a quarter had high 6‐TGN levels. One‐fourth of the patients needed dose modification. The dose‐based metabolite levels were comparable and the toxicity was less than that reported in Asian and Caucasian patients.

Minimal risk of lymphoma and non‐melanoma skin cancer despite long‐term use of thiopurines in patients with inflammatory bowel disease: A longitudinal cohort analysis from northern India

“…Compared with studies from the West and a study from India by Parkar et al . (8% myelosuppression rates), 35 higher rates of myelosuppression could be explained because of higher cut‐off of white blood cell count used for definition of leukopenia (< 4000 cells/mm 3 ) as compared with mentioned studies that defined leukopenia at leukocyte count of < 3000 cells/mm 3 . The median dose used in our cohort was 100 mg or 1.5 mg/kg, which is less compared with the recommended dose.…”

“…Myelosuppression is the commonest dose-dependent adverse event. The incidence of myelosuppression varies across the globe from as low as 5% in West to as high as 35.4% in Asians. 8 This variation can be attributed to the differential metabolism of thiopurines in different population owing to varying prevalence of thiopurine methyltransferase (TPMT) and nucleotide triphosphate diphosphatase 15 (NUDT 15) gene polymorphism, with TPMT being more common in Caucasians, and NUDT 15 gene polymorphism being more common in Asians.…”

Azathioprine-induced marrow suppression in dermatology patients - Analysis of 18 patients

“…[ 1 4 ] In a study from North India, 20 out of 114 patients with normal TPMT genotype developed marrow suppression. [ 5 ] No tests including TPMT genotype[ 5 ] or phenotype testing[ 6 ] can predict the risk of myelotoxicity by azathioprine accurately. Hence, regular monitoring of blood counts despite TPMT testing is essential.…”