Drug Insight: pharmacology and toxicity of thiopurine therapy in patients with IBD

Abstract

Thiopurines are frequently used for the treatment of IBD. The complex pharmacology, metabolism, mechanism of action and toxicity profile of these immunosuppressive drugs have now been partly elucidated. The activity of thiopurines is partly mediated by the metabolite 6-thioguanosine 5'-triphosphate, which inhibits the function of the small GTPase Rac1, leading to apoptosis of activated T cells, and influences the conjugation of T cells with antigen-presenting cells. The activity of the enzyme thiopurine S-methyltransferase has a major influence on the bioavailability and toxicity of thiopurines, and several thiopurine metabolites might have adverse effects in patients. Myelotoxicity can be caused by grossly elevated levels of 6-thioguanine nucleotides, and elevated levels of 6-methylmercaptopurine ribonucleotides have been associated with hepatotoxicity. The sensitivity and specificity of these methylated metabolites for predicting thiopurine-induced liver enzyme abnormalities are, however, poor. 6-Thioguanine has been suggested as an alternative to the classical thiopurines azathioprine and 6-mercaptopurine for the treatment of IBD, but there are concerns about its toxicity profile, especially with regard to the induction of nodular regenerative hyperplasia of the liver. Data now suggest that the induction of nodular regenerative hyperplasia of the liver during 6-thioguanine therapy might be dose-dependent or dependent on the level of 6-thioguanine nucleotides.

Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee

“…Th ere is a greater tendency for serious infections in patients with lower absolute lymphocyte counts or leukopenia ( 154 ). Th e frequency of liver abnormalities varies between 2 % and 17 % of patients and depends largely on the defi nitions of liver abnormalities reported ( 194 ). Th e liver test abnormalities are usually reversible and generally occur soon aft er the initiation of thiopurine treatment.…”

Thiopurine Prodrugs Mediate Immunosuppressive Effects by Interfering with Rac1 Protein Function

“…For example, our lack of understanding may hinder recognition of any side effects of 6-TGNP that may occur through its binding to other critical Rho GTPases such as RhoA and Cdc42. This notion arises because, although the previous study shows that 6-TGNP preferentially blocks the Vav action on Rac1 but not on RhoA and Cdc42 (11), Vav has a rather broad spectrum of catalytic specificity (22). Thus, Vav is capable of activating all of these Rho proteins, including Rac1, RhoA, and Cdc42.…”

“…They are widely used to treat autoimmune disorders such as inflammatory bowel disease and cancers such as acute lymphoblastic leukemia (1)(2)(3). In cells, enzymes convert the inactive prodrug 6-TP into pharmacologically active deoxy-6-thioguanosine phosphate (which is also called 6-thioguanine nucleotide) and 6-thioguanosine phosphate (6-TGNP), which includes 6-thioguanosine diphosphate (6-TGDP) and triphosphate (6-TGTP) (1)(2)(3)(4)(5)(6). The deoxy-6-thioguanosine phosphate derived from 6-TP prodrugs can be incorporated into de novo synthesis of DNA as a form of 6-TG.…”

A drug‐repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6‐thioguanine as an effective therapeutic agent for TPMT‐low cancer cells

“…Because 6‐TG has been shown to regulate GTPase activity (de Boer et al ., 2007), we analyzed the effect of 6‐TG on the RAS‐RAF‐MAP Kinase pathway that is frequently activated in PDAC. The results in Fig.…”