Pharmacological monitoring of azathioprine therapy.
BACKGROUND
Studies on azathioprine (Aza) treatment in Crohn disease have indicated a positive correlation between clinical remission and a concentration in erythrocytes of the metabolites 6-thioguanine nucleotides (E-6-TGN) above 230 pmol/8 x 10(8) RBC. A concentration of the methylated Aza metabolites (E-6-MMP) above 5000 pmol/8 x 10(8) RBC has been correlated to hepatotoxicity. Thiopurine methyltransferase (TPMT) is responsible for the formation of methylated metabolites and lower E-TGN levels, and TPMT genotyping has been proposed as guidance for dosage. In a cross-sectional study we investigated relationships between the clinical outcome and Aza dose, the TPMT genotype and the Aza metabolite levels among patients with Crohn disease.


METHODS
TPMT genotype (PCR assay), azathioprine metabolite levels (HPLC analysis) and xanthine oxidase (XO) activity were determined once in 71 randomly selected Crohn patients on an unaltered Aza dose for at least 3 months.


RESULTS
None of the doses of Aza, TPMT genotype, E-6-TGN-, E-6-MMP levels or XO activity were significantly related to disease activity (H-B score), (P = 0.18, P = 0.69, P = 0.90, P = 0.54, P = 0.29, respectively). Leucopenia and/or hepatotoxicity were not demonstrated in any patient. Four patients had a heterozygous TPMT genotype (6.1%; 95% CI: 1.68%-14.80%). The 4 TPMT heterozygous patients had higher E-6-TGN levels than did the 67 remaining patients (P = 0.008).


CONCLUSIONS
To explore the applicability of TPMT genotyping, E-6-TGN and E-6-MMP levels for therapeutic drug monitoring, large prospective studies with patient entry at the start of Aza therapy are needed. Until the results of such studies are available, the dose adjustments of Aza should be guided primarily by clinical response and blood counts; metabolite level measurements can only be applied to identify therapeutic non-compliance.
Reuther
L O
LO
Dept. of Clinical Pharmacology, Gentofte University Hospital, Hellerup, Denmark. lenereuther@hotmail.com
Sonne
J
J
Larsen
N E
NE
Larsen
B
B
Christensen
S
S
Rasmussen
S N
SN
Tofteng
F
F
Haaber
A
A
Johansen
N
N
Kjeldsen
J
J
Schmiegelow
K
K
D000328:Adult; D000368:Aged; D000963:Antimetabolites / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001379:Azathioprine / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003430:Cross-Sectional Studies; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D009325:Nausea / Q000209:etiology; D016896:Treatment Outcome
D000963:Antimetabolites; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine