Thiopurines in Inflammatory Bowel Disease - The Role of Pharmacogenetics and Therapeutic Drug Monitoring

Abstract

Pharmacogenetics represents the study of variability in drug response due to genetic variations. Inflammatory bowel disease (IBD, i.e. primarily Crohn's disease and ulcerative colitis) is characterized by a chronic or relapsing inflammation of the digestive tract. The thiopurines 6-mercaptopurine (6-MP) and azathioprine (AZA), an imidazol derivative and pro-drug of 6-MP, are widely used in IBD, particularly in Crohn's disease. The metabolism of thiopurines is complex and individually variable. Thiopurine methyltransferase (TPMT) is a key enzyme in this metabolism and exhibits a genetic variability due to a number of variant alleles coding for a defective enzyme. The formation of biologically active thioguanine nucleotides (TGN) and methylated metabolites may vary considerably due to the TPMT activity. Patients with decreased TPMT activity are at increased risk of developing severe side effects if treated with conventional thiopurine doses, due to the accumulation of toxic metabolites. Determination of the TPMT phenotype or genotype is often used to identify individuals with increased risk for adverse events. Twenty-one variant TPMT alleles have been described, of which three are more common than the others. An association between inosine triphosphate pyrophosphatase polymorphisms and adverse events during thiopurine treatment has also been proposed. In this review, the clinical value of TPMT status determination and pharmacological monitoring of thiopurine metabolites are discussed as well as the increased interest in the use of 6-thioguanine, a thiopurine with a less complex metabolism, as an alternative for patients who do not tolerate AZA or 6-MP. It can be concluded that TPMT determination before start of thiopurine therapy is of value to identify individuals with increased risk for adverse reactions due to genetic enzyme deficiency. However, large prospective studies are still needed to evaluate the true benefit of monitoring thiopurine metabolites during thiopurine treatment.

How are thiopurines used and monitored by Swedish gastroenterologists when treating patients with inflammatory bowel disease?

“…The thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) are the mainstay in this respect and they are increasingly and more liberally used in IBD [1]. These drugs have proven to be effective in both inducing and maintaining remission of Crohn's disease (CD) and ulcerative colitis (UC) [2,3].…”

“…AZA is converted to 6-MP, which after further metabolism results in the formation of active thioguanine nucleotides (TGN). Thiopurine S-methyltransferase (TPMT) is a key enzyme in the metabolism of thiopurine drugs, and genetic polymorphisms in the TPMT gene (TPMT *2 to *31) are associated with decreased TPMT activity and the development of myelotoxicity due to high TGN metabolite concentrations [1]. A pretreatment TPMT determination will ensure that TPMT-deficient patients are not exposed to a dangerous treatment with the potential of life-threatening complications [4].…”

“…A pretreatment TPMT determination will ensure that TPMT-deficient patients are not exposed to a dangerous treatment with the potential of life-threatening complications [4]. It can also be used as a guide for thiopurine dosage and thus ensures that TPMT heterozygotes are treated with a reduced dose, thereby preventing dose-related leucopenia [1].…”

Novel Strategies in the Thiopurine Treatment of Inflammatory Bowel Disease

“…[20] The methylated metabolite, methylthioinsoine 5 -monophosphate (meTIMP), synthetized from thioinosine monophosphate (TIMP) by methylation of the polymorphic enzyme thiopurine S-methyltransferase (TPMT) 274 S. Almer causes immunosuppression by inhibition of the purine-de-novo biosynthesis as demonstrated in vitro. [1] Aminosalicylates inhibit TPMT in vitro and it has therefore been proposed that active introduction of cotherapy would be beneficial in patients unresponsive to thiopurines. However, even if some clinical data show a moderate increase in TGN levels under concomitant treatment with aminosalicylates, [21] this strategy has not yet been proven to be of any real clinical benefit to patients.…”

“…These therapies are inefficient or limited by adverse drug reactions in about half of the patients, and therefore, at least in specialized centers, about 50% of IBD patients are qualified for long-term immunomodulation. The thiopurine drugs are the mainstay in this respect and they are increasingly and more liberally used in IBD (see review [1] ).…”