Premium
Biotransformation of 6‐thioguanine in inflammatory bowel disease patients: a comparison of oral and intravenous administration of 6‐thioguanine
Author(s) -
Jharap B,
de Boer NKH,
Vos RM,
Smid K,
Zwiers A,
Peters GJ,
Mulder CJJ,
Wilhelm AJ,
van Bodegraven AA
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01265.x
Subject(s) - xanthine oxidase , hypoxanthine , pharmacokinetics , allopurinol , thiopurine methyltransferase , pharmacology , azathioprine , area under the curve , inflammatory bowel disease , medicine , mercaptopurine , dosing , oral administration , chemistry , gastroenterology , biochemistry , enzyme , disease
BACKGROUND AND PURPOSE 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 APPROACH In 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 RESULTS The median AUC per mg 6‐TG was 1068 (p.o.) and 7184 (i.v.) pmol·h (8 × 10 8 RBC) −1 . 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). CONCLUSIONS AND IMPLICATIONS The great variability of the AUC per mg for 6‐TG observed after p.o. and i.v. administration of 6‐TG, was partly explained by variability in activities of metabolizing enzymes. Exposure of 6‐TGN was low in all patients.