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. 2001 Nov;49(5):656–664. doi: 10.1136/gut.49.5.656

Leucopenia resulting from a drug interaction between azathioprine or 6-mercaptopurine and mesalamine, sulphasalazine, or balsalazide

P Lowry 1, C Franklin 1, A Weaver 1, C Szumlanski 1, D Mays 1, E Loftus 1, W Tremaine 1, J Lipsky 1, R Weinshilboum 1, W Sandborn 1
PMCID: PMC1728490  PMID: 11600468

Abstract

AIM—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 109/l and ⩽3.5×109/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 ⩽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.


Keywords: azathioprine; 6-mercaptopurine; inflammatory bowel disease; leucopenia; mesalamine; sulphasalazine; balsalazide

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Figure 1  .

Figure 1  

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Percentage of patients with Crohn's disease with clinically important leucopenia, according to treatment group. All significant differences between week 0 and subsequent time points for each of the treatment groups are indicated. (A) Clinically important leucopenia (white blood cell (WBC) count <3.0×109/l) at any time during the study. (B) Clinically important leucopenia (WBC count ⩽ 3.5×109/l) at any time during the study. The 95% confidence intervals for this end point for the mesalamine, sulphasalazine, and balsalazide groups are 19-81%, 23-83%, and 3-56%, respectively. (C) Clinically important leucopenia (WBC count <3.0×109/l) over eight weeks. (D) Clinically important leucopenia (WBC count ⩽3.5×109/l) over eight weeks.

Figure 2  .

Figure 2  

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Mean values at each study visit according to treatment group. Both significant and non-significant differences between week 0 and subsequent time points for each of the treatment groups are indicated. (A) Total white blood cell (WBC) concentrations. (B) Whole blood 6-thioguanine nucleotide (6-TGN) concentrations. Mean (95% confidence intervals) change from baseline for whole blood 6-TGN (pmol/8×108 RBCs) in the mesalamine group at weeks 2, 4, 6, and 8 were: 74 (11-136), 71 (36-106), 55 (−1-110), and 43 (8-77). Mean (95% confidence intervals) change from baseline for whole blood 6-TGN (pmol/8×108 RBCs) in the sulphasalazine group at weeks 2, 4, 6, and 8 were: 29 (10-48), 20 (1-39), 30 (−10-70), and 38 (−1-77). Mean (95% confidence intervals) change from baseline for whole blood 6-TGN (pmol/8×108 RBCs) in the balsalazide group at weeks 2, 4, 6, and 8 were: 16 (−1-33), 16 (1-31), 15 (−4-33), and −1 (−32-31). (C) Duodenal mucosal 6-TGN concentrations. (D) Red blood cell thiopurine methyltransferase (TPMT) activity.

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