Monitoring of long-term thiopurine therapy among adults with inflammatory bowel disease.
BACKGROUND
The immunosuppressive effects of thiopurine drugs are mainly mediated through their intracellular metabolism into active 6-thioguanine nucleotide (6-TGN) metabolites, which are incorporated into DNA. Erythrocyte 6-TGN (E-6TGN) levels have been proposed as an instrument for monitoring treatment. The aim of the study was to use erythrocyte E-6TGN, methylated mercaptopurine (MeMP) metabolites, and thiopurine methyltransferase (TPMT) measurements in a clinical setting to determine the clinical outcome in relation to thiopurine metabolism.


METHODS
Fifty-five adult patients with inflammatory bowel disease were included in a prospective study and followed for 6 months. Metabolite levels were measured and correlated to outcome and AZA/6-MP dose.


RESULTS
The E-6TGN level was significantly related to the TPMT genotype (P = 0.008). Patients in disease remission had higher E-6TGN levels than patients with disease activity both at baseline (P < 0.05) and after 6 months (P = 0.02). Active disease was more frequent among subjects with E-6TGN < or = 125 nmol/mmol Hb at baseline (P = 0.04), but not at 6 months. AZA/6-MP drug dose was positively correlated to E-MeMP levels (r = 0.48; P < 0.001) and E-MeMP/E-6TGN ratio (r = 0.41; P = 0.002). Dose changes were positively correlated with the changes in E-MeMP levels (P = 0.01) and E-MeMP/E-6TGN ratio (P = 0.03).


CONCLUSIONS
E-6TGN level was the only factor in this study related to disease activity, while there was no relationship between AZA/6-MP dose and E-6TGN levels. This finding illustrates the clinical usefulness of E-6TGN monitoring in the evaluation of treatment intensity.
Hindorf
U
U
Section of Gastroenterology, Department of Internal Medicine, Blekinge Hospital, Karlskrona, Sweden. Ulf.Hindorf@med.lu.se
Lyrenäs
E
E
Nilsson
A
A
Schmiegelow
K
K
D000293:Adolescent; D000328:Adult; D001379:Azathioprine / Q000009:adverse effects / Q000627:therapeutic use*; D016903:Drug Monitoring; D004912:Erythrocytes / Q000737:chemistry; D005260:Female; D005838:Genotype; D006150:Guanine Nucleotides / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D008780:Methyltransferases / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D012460:Sulfasalazine / Q000627:therapeutic use; D013873:Thionucleotides / Q000097:blood
D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D012460:Sulfasalazine; C010240:6-methylthiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine