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The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients
Author(s) -
GILISSEN L. P. L.,
BIERAU J.,
DERIJKS L. J. J.,
BOS L. P.,
HOOYMANS P. M.,
GENNIP A.,
STOCKBRÜGGER R. W.,
ENGELS L. G. J. B.
Publication year - 2005
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/j.1365-2036.2005.02630.x
Subject(s) - thiopurine methyltransferase , mesalazine , medicine , mercaptopurine , pharmacology , inflammatory bowel disease , azathioprine , discontinuation , gastroenterology , pharmacokinetics , disease
Summary Background : In vitro studies suggest interactions between mesalazine (mesalamine) and thiopurines by thiopurine S ‐methyltransferase (TPMT) inhibition, influencing the balance of hepatotoxic 6‐methylmercaptopurine ribonucleotide and immunosuppressive tioguanine (thioguanine) metabolites. Aim : To examine the in vivo pharmacokinetic interaction between mesalazine and mercaptopurine. Methods : A prospective study was performed in quiescent inflammatory bowel disease patients using the combination of mercaptopurine and mesalazine. Laboratory parameters, 6‐methylmercaptopurine ribonucleotide and tioguanine levels and thiopurine S ‐methyltransferase activity in erythrocytes were measured at stable medication, after mesalazine discontinuation and mesalazine reintroduction, further mercaptopurine was continued. Results : Seventeen patients were participated. Mean mercaptopurine dose was 0.78 mg/kg/day and median of mesalazine dose was 3000 mg/day. After mesalazine discontinuation, mean tioguanine levels changed significantly from 262 to 209 pmol/8 × 10 8 red blood cell, increasing to 270 after reintroduction. Mean 6‐methylmercaptopurine ribonucleotide levels were 1422, 2149 and 1503 pmol/8 × 10 8 red blood cell respectively. Mean 6‐methylmercaptopurine ribonucleotide/tioguanine ratio increased significantly from 6.3 at baseline to 11.2. Mean baseline thiopurine S ‐methyltransferase activity was 0.58 pmol/10 6 red blood cell/h and stable. All patients had wild‐type thiopurine S ‐methyltransferase genotypes however, leucocyte counts were stable. Discussion : A significantly higher tioguanine levels and improving 6‐methylmercaptopurine ribonucleotide/tioguanine ratio were found during mesalazine/mercaptopurine combination. Theoretically, mesalazine inhibits thiopurine S ‐methyltransferase activity. In vivo thiopurine S ‐methyltransferase activity did not change, however. Conclusion : Mesalazine has synergistic effects on mercaptopurine therapy, but the mechanism is unclear. Combining these drugs may be further indication for mesalazine in inflammatory bowel disease treatment.