Biotransformation of 6‐thioguanine in inflammatory bowel disease patients: a comparison of oral and intravenous administration of 6‐thioguanine

Abstract

Although 6-mercaptopurine and azathioprine are effective treatments in inflammatory bowel disease (IBD), many patients discontinue treatment because of side effects. 6-Thioguanine (6-TG) may be an alternative rescue therapy in these intolerant patients but the pharmacokinetics of 6-TG are not fully described. Here we have measured the pharmacokinetics of the biotransformation of 6-TG into the pharmacologically active metabolites, 6-thioguanine nucleotides (6-TGN), in IBD patients. EXPERIMENTAL APPROACHIn 12 patients with IBD, levels of 6-TGN and activities of thiopurine S-methyltransferase, xanthine oxidase and hypoxanthine guanine-phosphoribosyl-transferase were measured in a two-stage (i.v. and p.o. administration of 0.3 mg·kg -1 6-TG), prospective study. Median exposure of 6-TGN in red blood cells (RBC) was expressed as the ratio of the area under the curve (AUC) per mg 6-TG after i.v. dosing and that after p.o. dosing. KEY RESULTSThe median AUC per mg 6-TG was 1068 (p.o.) and 7184 (i.v.) pmol·h (8 ¥ 10 8 RBC). Median exposure of 6-TGN in RBC was 15% (9-28). Hypoxanthine guanine-phosphoribosyl-transferase activity correlated with peak 6-TGN and with AUC per mg (r = 0.7, P = 0.02 and r = 0.6, P = 0.03 respectively). Thiopurine S-methyltransferase activity was inversely related to AUC per mg (r = -0.8, P = 0.001), whereas that of xanthine oxidase was correlated with a lower peak 6-TGN (r = -0.7, P = 0.02).

Clinical Value of Mercaptopurine After Failing Azathioprine Therapy in Patients With Inflammatory Bowel Disease

“…Furthermore, our centre is a dedicated thiopurine research centre. (5,6,12,(27)(28)(29)(30)(31)(32) Before cessation of thiopurines, we attempt to optimize therapy first by: split-dose administration, therapeutic drug monitoring (TDM) or specific analyses concerning other potential culprits of witnessed AE, being all factors potentially contributing to a more disadvantageous therapeutic outcome.…”

Pharmacogenomics and personalized medicine: a review focused on their application in the Chinese population

“…This enzyme, which is predominantly expressed in the intestinal mucosa and liver, converts 6-MP to 6-TX and subsequently to the inactive metabolite 6-TU [124,125] , a principal pathway in 6-MP catabolism. However, research on XO genetic polymorphisms and azathioprine toxicities is sparse and no significant correlation has been established [122,126] .…”

Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease

“…Red blood cells (RBCs) were isolated by centrifugation at approximately 1740 g. The plasma and buffy coat were separated and RBCs were washed thoroughly with phosphate buffer saline (PBS). The cell count was determined on Sysmex XN‐2000 Model & Serial No: 1369/13640/11538 (Millipore) and samples were stored at −20°C until analysis 22, 23…”

“…After vortex mixing the samples, 70% perchloric acid was added to the mixture. The samples were then centrifuged at 3000 g for 10 min and the supernatant was further hydrolyzed in boiling water bath for 1 h. Hydrolysate was filtered with 0.2‐μm syringe filters and 50 μL of it was injected into HPLC system 23, 24…”