The pharmacokinetic effect of discontinuation of mesalazine on mercaptopurine metabolite levels in inflammatory bowel disease patients.
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.


OBJECTIVE
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 x 10(8) red blood cell, increasing to 270 after reintroduction. Mean 6-methylmercaptopurine ribonucleotide levels were 1422, 2149 and 1503 pmol/8 x 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.


CONCLUSIONS
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.


CONCLUSIONS
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.
Gilissen
L P L
LP
Department of Gastroenterology and Hepatology, University Hospital Maastricht, Maastricht, the Netherlands. lgi@sint.azm.nl
Bierau
J
J
Derijks
L J J
LJ
Bos
L P
LP
Hooymans
P M
PM
van Gennip
A
A
Stockbrügger
R W
RW
Engels
L G J B
LG
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D000963:Antimetabolites / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism; D004338:Drug Combinations; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism; D015122:Mercaptopurine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019804:Mesalamine / Q000008:administration & dosage / Q000494:pharmacology*; D011446:Prospective Studies; D013866:Thioguanine / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000963:Antimetabolites; D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D019804:Mesalamine; D015122:Mercaptopurine; D013866:Thioguanine