6-thioguanosine diphosphate and triphosphate levels in red blood cells and response to azathioprine therapy in Crohn's disease.
OBJECTIVE
Azathioprine is the gold standard for immunosuppressive therapy in Crohn's disease (CD) and its molecular mechanism of action is caused by the metabolite 6-thioguanosine triphosphate (TGTP). In this study we assessed the impact of TGTP levels for monitoring of azathioprine therapy.


METHODS
A novel, highly sensitive assay was established to measure levels of TGTP and its precursors 6-thioguanosine monophosphates and 6-thioguanosine diphosphates (TGDP) in red blood cells from 50 CD patients. The results were correlated with clinical outcome.


RESULTS
TGTP levels could be quantified in 47 patients and a subgroup of these patients showed significantly high levels of TGDP. 6-thioguanine nucleotide (6-TGN) levels showed a significant correlation with TGDP plus TGTP concentrations, suggesting that active TGTP and its inactive precursor TGDP are the main metabolites within 6-TGN. Patients with 6-TGN levels higher than 100 pmol/8x10(8) red blood cells showed better response rates, on average, than patients with lower 6-TGN levels. The subgroup of patients with higher 6-TGN and increased TGDP levels showed a worse outcome with lower response rates, more flares, and higher infliximab demand than patients with high 6-TGN, low TGDP, and predominantly detectable TGTP levels.


CONCLUSIONS
This study shows that quantification of TGTP levels can be used to monitor azathioprine therapy in inflammatory bowel disease patients. Furthermore, the data suggest that TGDP levels of more than 15% of total 6-TGN levels may be a useful surrogate parameter to predict poor response in a subgroup of azathioprine-treated patients.
Neurath
Markus F
MF
Medical Clinic, University of Mainz, Mainz, Germany. neurath@1-med.klinik.uni-mainz.de
Kiesslich
Ralf
R
Teichgräber
Ute
U
Fischer
Christine
C
Hofmann
Ute
U
Eichelbaum
Michel
M
Galle
Peter R
PR
Schwab
Matthias
M
D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001379:Azathioprine / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D003424:Crohn Disease / Q000097:blood* / Q000188:drug therapy*; D004912:Erythrocytes / Q000737:chemistry*; D006150:Guanine Nucleotides / Q000097:blood*; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives* / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D000069285:Infliximab; D013873:Thionucleotides / Q000097:blood*
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; D006153:Guanosine Diphosphate; C003964:6-thioguanylic acid; C032829:6-thioguanosine 5'-diphosphate; D000069285:Infliximab; D001379:Azathioprine