Hepatotoxicity of 6-mercaptopurine (6-MP) and Azathioprine (AZA) in adult IBD patients.
OBJECTIVE
6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15% of pediatric patients and has been associated with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 x 10(8) RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients.


METHODS
Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis.


RESULTS
Eight patients (4.6%) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 x 10(8) RBC versus 3,452 pmol/8 x 10(8) RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4%vs 2.3%, P < 0.05); however, nearly 90% of all patients with 6-MMPR > 5,300 pmol/8 x 10(8) RBC had no hepatotoxicity, while almost 40% of subjects with hepatotoxicity had 6-MMPR levels below this cutoff.


CONCLUSIONS
6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.
Shaye
Omid A
OA
Division of Gastroenterology, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.
Yadegari
Michael
M
Abreu
Maria T
MT
Poordad
Fred
F
Simon
Karen
K
Martin
Paul
P
Papadakis
Konstantinos A
KA
Ippoliti
Andrew
A
Vasiliauskas
Eric
E
Tran
Tram T
TT
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000963:Antimetabolites / Q000009:adverse effects* / Q000378:metabolism; D001379:Azathioprine / Q000009:adverse effects* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008111:Liver Function Tests; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000378:metabolism; D008875:Middle Aged; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
D000963:Antimetabolites; D015122:Mercaptopurine; D001379:Azathioprine