Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease

doi:10.1111/j.1365-2036.2004.01947.x

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Wiley InterScience

Alimentary Pharmacology & Therapeutics

Volume 19 Issue 12, Pages 1269 - 1276

Published Online: 4 Jun 2004

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Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease

K. R. Herrlinger*, K. Fellermann*, C. Fischer†, W. kreisel‡, P. Deibert‡, J. Schoelmerich§, W. E. Fleig¶, A. Ruhl**, M. Reinshagen††, R. Greinwald‡‡, E. F. Stange* & M. Schwab†

*Department of Gastroenterology, Hepatology and Endocrinology, Robert-Bosch-Hospital, Stuttgart, Germany ; †Dr Margarete-Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany ; ‡Department of Internal Medicine II, Albert-Ludwigs-University, Freiburg, Germany ; §Department of Internal Medicine, University of Regensburg, Germany ; ¶1st Department of Medicine, Martin-Luther-University, Halle, Germany ; **Department of Gastroenterology, Karl-Ruprechts-University, Heidelberg, Germany ; ††Department of Medicine I, Albert-Einstein-University, Ulm, Germany ; ‡‡Dr Falk-Pharma GmbH, Freiburg, Germany

Correspondence to Dr K. R. Herrlinger, Department of Gastroenterology, Hepatology and Endocrinology, Robert-Bosch-Hospital, Auerbachstrasse 110, D-70376 Stuttgart, Germany.
E-mail: klaus.herrlinger@rbk.de

Summary

Background: 6-Thioguanine-nucleotides seem to be the active metabolites of thiopurine therapy, and their monitoring has been considered a useful tool for optimizing response in inflammatory bowel diseases. Tioguanine (thioguanine) therapy results in much higher levels of 6-thioguanine-nucleotide levels when compared with azathioprine or mercaptopurine.

Aim: To elucidate the influence of 6-thioguanine-nucleotide and methylated 6-thioguanine-nucleotide levels under tioguanine on efficacy and toxicity in Crohn's disease.

Methods: 6-Thioguanine-nucleotide and methylated 6-tioguanine-nucleotide levels were measured regularly in 26 Crohn's disease patients treated with tioguanine. Nucleotide levels were related to efficacy and toxicity.

Results: 6-Thioguanine-nucleotide levels rose very high [median 1241 pmol/8 × 10⁸ red blood cells (range 313–1853)]. Methylated 6-thioguanine-nucleotide levels were detected in all patients [491 pmol/8 × 10⁸ red blood cells (154–1775)]. 6-Thioguanine-nucleotide and methylated 6-thioguanine-nucleotide concentrations correlated significantly (r = 0.7, P < 0.0001). Nucleotide levels from patients achieving remission (n = 14) did not differ significantly from non-remitters (n = 12) [6-thioguanine-nucleotide: 1077 (599–2160) vs. 1210 (534–4665); methylated 6-thioguanine-nucleotide: 510 (214–1222) vs. 421 (145–1284)]. One patient with intermediate thiopurine S-methyltransferase activity experienced bone marrow toxicity upon dose escalation parallel with excessively high thioguanine-nucleotide levels.

Conclusions: 6-Thioguanine-nucleotide as well as methylated 6-thioguanine-nucleotide levels under tioguanine therapy were not related to efficacy. This suggests that monitoring of 6-thioguanine-nucleotide levels is not a useful tool to predict response to thiopurines.

Accepted for publication 17 March 2004

DIGITAL OBJECT IDENTIFIER (DOI)

10.1111/j.1365-2036.2004.01947.x About DOI