On therapeutic drug monitoring of thiopurines in inflammatory bowel disease; pharmacology, pharmacogenomics, drug intolerance and clinical relevance.
Thiopurines such as azathioprine, 6-mercaptopurine and 6-thioguanine are antimetabolites that have been used for several decades in the treatment of several diseases including inflammatory bowel diseases. Additional anti-inflammatory properties of these thiopurines have been discovered in recent years. Thiopurine metabolism is complex due to the involvement of multiple enzymes, of which the activities are genetically determined and cell type dependent. Single nucleotide polymorphisms in the genes encoding these enzymes have been correlated with altered activities and drug intolerance. Detailed implications of these will be reviewed. Over the years several methods of therapeutic drug monitoring have been developed in an attempt to relate thiopurine drug availability with efficacy and intolerance. In this respect, monitoring pharmacologically active 6-thioguanine nucleotide concentrations is most widely used. So far, however, the clinical usefulness of these methods is hampered by methodological limitations. Some drug interactions may optimize the metabolization of thiopurines and consequently increase its efficacy and decrease drug intolerance. This review focuses on the clinical relevance and usefulness of therapeutic drug monitoring of thiopurines and provides suggestions to optimize thiopurine therapy in the treatment of inflammatory bowel diseases.
Van Asseldonk
Dirk P
DP
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, The Netherlands. d.vanasseldonk@vumc.nl
de Boer
Nanne K H
NK
Peters
Godefridus J
GJ
Veldkamp
Agnes I
AI
Mulder
Chris J
CJ
Van Bodegraven
Ad A
AA
D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001711:Biotransformation / Q000235:genetics; D004347:Drug Interactions; D016903:Drug Monitoring; D005765:Gastrointestinal Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D017410:Practice Guidelines as Topic; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D013438:Sulfhydryl Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D005765:Gastrointestinal Agents; D011687:Purines; D013438:Sulfhydryl Compounds