Thiopurine metabolism monitoring: implications in inflammatory bowel diseases.
BACKGROUND
Thiopurines (TP) are widely used in the management of inflammatory bowel diseases. Side effects and inefficacy are a major concern as they lead to withdrawal of the drug.


METHODS
Tools investigating TP metabolism are useful to avoid inadequate cessation of TP therapy.


RESULTS
TP metabolism is complex and many enzymes are involved. Among them, Thiopurine methyl transferase is the only one routinely measured by pheno- or genotyping. A decreased TPMT activity results in a potential overdosing of TP drugs leading to myelotoxicity, whereas an ultra-high activity leads to TP ineffectiveness and overproduction of methylated compounds responsible for hepatotoxicity. TPMT determination prior to TP treatment results in an individual adapted dose. Xanthine oxidase/dehydrogenase (XOD), inosine triphosphate pyrophosphatase (ITPA) and glutathion-S-transferase (GST) are other promising enzyme targets that might help to explain TP efficacy or toxicity. ITPA and GST polymorphisms might potentially be related to some TP side effects, while a XOD inhibition by allopurinol could avoid TP-related hepatotoxicity.


CONCLUSIONS
Utilization of thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is discussed, specifically, in case of thiopurine failure and recommendations are given about their interpretation and potential dose optimization. These enzymes and metabolites tests are complementary to the regular monitoring of blood cells count and liver tests which remains mandatory.
Dewit
Olivier
O
St. Luc University Hospital, Catholic University of Louvain Brussels, Brussels, Belgium CHU Saint-Etienne, Saint-Etienne, France. Olivier.Dewit@uclouvain.be
Starkel
Peter
P
Roblin
Xavier
X
D000963:Antimetabolites / Q000009:adverse effects* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005765:Gastrointestinal Agents / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000009:adverse effects* / Q000494:pharmacology; D013873:Thionucleotides / Q000009:adverse effects* / Q000494:pharmacology
D000963:Antimetabolites; D005765:Gastrointestinal Agents; D011687:Purines; D013873:Thionucleotides; D008780:Methyltransferases; C022745:thiopurine methyltransferase