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


OBJECTIVE
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 x 10(8) red blood cells (range 313-1853)]. Methylated 6-thioguanine-nucleotide levels were detected in all patients [491 pmol/8 x 10(8) 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.
Herrlinger
K R
KR
Department of Gastroenterology, Hepatology and Endocrinology, Robert-Bosch-Hospital, Stuttgart, Germany. klaus.herrlinger@rbk.de
Fellermann
K
K
Fischer
C
C
Kreisel
W
W
Deibert
P
P
Schoelmerich
J
J
Fleig
W E
WE
Ruhl
A
A
Reinshagen
M
M
Greinwald
R
R
Stange
E F
EF
Schwab
M
M
D000328:Adult; D015415:Biomarkers / Q000097:blood; D003424:Crohn Disease / Q000097:blood / Q000188:drug therapy*; D016903:Drug Monitoring / Q000379:methods; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D012074:Remission Induction; D013866:Thioguanine / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D013873:Thionucleotides / Q000097:blood*; D016896:Treatment Outcome
D015415:Biomarkers; D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D013866:Thioguanine