Interaction of ribavirin with azathioprine metabolism potentially induces myelosuppression.
BACKGROUND
The interaction of ribavirin, an inosine monophosphate dehydrogenase inhibitor, with azathioprine metabolism, potentially leading to myelotoxicity, remains unexplored.


OBJECTIVE
To underline the interaction of ribavirin, an inosine monophosphate dehydrogenase inhibitor, with azathioprine metabolism, potentially leading to myelotoxicity.


METHODS
The medical records of eight patients who developed severe pancytopenia following concomitant use of azathioprine and ribavirin were retrospectively reviewed.


RESULTS
Bone marrow suppression reached nadir after a mean interval of 4.6 +/- 1.6 weeks following HCV therapy initiation in seven patients. At the time of pancytopenia, the mean platelet count was 69.75 +/- 82.8 x 10(-3)/mm(3), mean haemoglobin level 7.75 +/- 1.3 g/dL and mean neutrophil count 0.45 +/- 0.26 x 10(-3)/mm(3). All patients had normal thiopurine methyltransferase genotype. In two patients, a prospective monitoring of azathioprine metabolites was available. Myelotoxicity was accompanied by elevated total methylated metabolite levels (16,500 and 15,000 pmol/8 x 10(8) erythrocytes) with a concomitant decrease in 6-tioguanine nucleotide levels; 1 month after azathioprine, pegylated interferon alfa and ribavirin were discontinued and full blood count returned to normal in both patients. No haematological toxicity occurred after the reintroduction of peginterferon plus ribarivin or azathioprine alone in eight patients.


CONCLUSIONS
Collectively, the benefit/risk ratio favours avoidance of inosine monophosphate dehydrogenase inhibitors in purine analogue-treated patients with normal thiopurine methyltransferase activity, a situation frequently encountered in clinical practice.
Peyrin-Biroulet
L
L
INSERM, U724, and Department of Hepato-Gastroenterology, University Hospital of Nancy, Vandoeuvre-les-Nancy, France.
Cadranel
J-F
JF
Nousbaum
J-B
JB
Oussalah
A
A
Seddik
M
M
Canva
V
V
Cortot
A
A
Sogni
P
P
Gueant
J-L
JL
Bigard
M-A
MA
Roblin
X
X
Bronowicki
J-P
JP
D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects*; D001379:Azathioprine / Q000009:adverse effects; D004347:Drug Interactions; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010198:Pancytopenia / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D010976:Platelet Count; D012189:Retrospective Studies; D012254:Ribavirin / Q000009:adverse effects; D012307:Risk Factors
D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D012254:Ribavirin; D001379:Azathioprine