Steering Azathioprine Safely: Lessons
From Pharmacogenetics
Cuffari C, Hunt S, Bayless T
Utilisation of Erythrocyte 6-Thioguanine Metabolite Levels to
Optimise Azathioprine Therapy in Patients With Inflammatory
Bowel Disease
Gut 2001;48:642– 6
ABSTRACT
The immunosuppressive properties of azathioprine and
6-mercaptopurine are mediated by their active metabolite
6-thioguanine. Cuffari and colleagues performed a prospec-
tive study to determine the relationship of erythrocyte
6-thioguanine levels and treatment efficacy in adult patients
with inflammatory disease (IBD). The study design is sum-
marized in Figure 1. Eighty-two patients (42 females) with
IBD aged 17–77 yr (mean age = 42) were studied. Among
63 with Crohn’s disease (CD) 29 had ileocolonic disease (15
with previous bowel resection) and 26 had colonic disease
(four with previous resection). Twelve of the 19 with ulcer-
ative colitis (UC) had pancolitis and the rest had left-sided
disease. The mean duration of IBD was 6.3 yr, and 72
patients were on 5-aminosalicylate. In patients with CD,
activity was measured using the Harvey-Bradshaw index
and for UC a clinical activity score was adapted to monitor
response to therapy. Remission was defined as an HBI score
of 5 in those who were weaned off on 20 mg/alternate
day of prednisolone or 3 mg/alternate day of budesonide.
Daily azathioprine of 1–1.5 mg/kg or an equivalent dose of
6-mercaptopurine was started on each patient. The levels of
6-thioguanine metabolites were measured while one was on
treatment for at least 12 wk. The erythrocyte 6-thioguanine
level was measured by reverse phase high performance
liquid chromatography.
Thirty-three patients with CD and 14 with UC achieved
remission at an average daily dose of 1.44 mg of azathio-
prine or 1.16 mg of 6-mercaptopurine. The median 6-thio-
guanine level for CD patients in remission was 316 pmol/
8 10
8
red blood cells (RBCs), compared with 176 pmol/
8 10
8
RBCs in those with incomplete responses. A
significantly higher number of patients who responded to
therapy had 6-thioguanine levels of 250 pmol/8 10
8
RBCs relative to those who failed to achieve remission.
Treatment efficacy correlated with a 6-thioguanine level of
250 pmol/8 10
8
RBCs in patients with colonic and
fistulating CD, but not in those with ileocolonic CD. Twen-
ty-two out of 30 patients with CD who were incompletely
responsive and had 6-thioguanine levels below 250 pmol/
8 10
8
RBCs were recruited to the dose optimization study.
The dose of azathioprine was increased by 25 mg/day at
8-wk intervals up to a median dose of 1.5 mg/kg/day. This
was associated with a rise in the median 6-thioguanine level
to 303 pmol/8 10
8
RBCs. Eighteen out of 22 patients
achieved remission on this regime.
The authors conclude that serial measurements of 6-thio-
guanine levels would be useful in optimizing azathioprine
treatment without inducing leucopenia. Patients who were
unresponsive to therapy despite adequate 6-thioguanine lev-
els (250 pmol/8 10
8
RBCs) should be considered re-
fractory to azathioprine/6-mercaptopurine and offered other
forms of treatment. (Am J Gastroenterol 2001;96:
3202–3203. © 2001 by Am. Coll. of Gastroenterology)
COMMENTS
Immunomodulatory therapy with azathioprine and 6-mer-
captopurine has been shown to be effective in steroid-
dependent and resistant cases of inflammatory bowel dis-
ease (IBD) (1). It has been suggested that 6-mercaptopurine
is the most cost-effective way to maintain remission after
surgery for Crohn’s disease (CD). Despite the proven effi-
cacy of azathioprine and its metabolite 6-mercaptopurine, a
delay of 7–14 wk before the onset of therapeutic benefit and
concerns regarding drug-induced toxicity have limited their
use in IBD. Once absorbed, azathioprine is converted to
6-mercaptopurine by a nonenzymatic reaction (Fig. 2).
6-Mercaptopurine is rapidly taken up by erythrocytes and
organ tissues. Intracellular biotransformation of 6-mercap-
topurine occurs along two competing routes. The drug is
catabolized into inactive 6-methylmercaptopurine by thio-
purine methyl transferase (TPMT) or anabolized to the
active 6-thioguanine nucleotide by the hypoxanthine phos-
phoribosyltransferase pathway. Incorporation of 6-thiogua-
nine into lymphocyte DNA induces cytotoxicity and immu-
nosuppression. Initial reports in lymphoblastic leukemia
suggested that the 6-thioguanine level could influence dis-
ease-free survival, independent of other factors that effect
prognosis (2, 3). A recent study in 92 pediatric patients with
Figure 1. Study design. AZA = azathioprine; 6-MP = 6-mercap-
topurine.
3202 World Literature Review AJG – Vol. 96, No. 11, 2001