Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide.
OBJECTIVE
We evaluated the effect of coadministration of sulphasalazine, mesalamine, and balsalazide on the pharmacokinetics and pharmacodynamics of azathioprine and 6-mercaptopurine.


METHODS
Thirty four patients with Crohn's disease receiving azathioprine or 6-mercaptopurine were enrolled in an eight week non-randomised parallel group drug interaction study and treated with mesalamine 4 g/day, sulphasalazine 4 g/day, or balsalazide 6.75 g/day. The primary outcome measure was the occurrence of clinically important leucopenia during the study, defined separately as total leucocyte counts < 3.0 x 10(9)/l and < or = 3.5 x 10(9)/l. Whole blood 6-thioguanine nucleotide concentrations were determined.


RESULTS
Three patients could not be evaluated for the primary outcome measure. In the remaining 31 patients, the frequency of total leucocyte counts < 3.0 and < or = 3.5 were: 1/10 and 5/10 in the mesalamine group; 1/11 and 6/11 in the sulphasalazine group; and 0/10 and 2/10 in the balsalazide group. There were significant increases in mean whole blood 6-thioguanine nucleotide concentrations from baseline at most time points in the mesalamine and sulphasalazine groups but not in the balsalazide group.


CONCLUSIONS
In patients with Crohn's disease receiving azathioprine or 6-mercaptopurine, coadministration of mesalamine, sulphasalazine, and possibly balsalazide results in an increase in whole blood 6-thioguanine nucleotide concentrations and a high frequency of leucopenia.
Lowry
P W
PW
Division of Gastroenterology, Division of Clinical Pharmacology, Department of Pharmacology, and Section of Biostatistics, Mayo Clinic, Rochester, MN, USA.
Franklin
C L
CL
Weaver
A L
AL
Szumlanski
C L
CL
Mays
D C
DC
Loftus
E V
EV
Tremaine
W J
WJ
Lipsky
J J
JJ
Weinshilboum
R M
RM
Sandborn
W J
WJ
D000328:Adult; D000636:Aminosalicylic Acids / Q000009:adverse effects; D000704:Analysis of Variance; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001379:Azathioprine / Q000009:adverse effects; D016010:Binomial Distribution; D002851:Chromatography, High Pressure Liquid; D016001:Confidence Intervals; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007970:Leukopenia / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects; D019804:Mesalamine / Q000009:adverse effects; D008780:Methyltransferases / Q000097:blood; D010659:Phenylhydrazines; D012460:Sulfasalazine / Q000009:adverse effects; D013866:Thioguanine / Q000032:analysis
D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D010659:Phenylhydrazines; D012460:Sulfasalazine; D019804:Mesalamine; D015122:Mercaptopurine; D008780:Methyltransferases; D013866:Thioguanine; D001379:Azathioprine; C038637:balsalazide