Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

Abstract

Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (IBD). This review focuses on the metabolism and mode of action of thiopurines and MTX, and provides an updated overview of individualized treatment strategies in which efficacy in IBD can be increased without compromising safety. The patient-based monitoring instruments adapted into clinical practice include pretreatment thiopurine S-methyltransferase testing, thiopurine metabolite monitoring, and blood count measurements that may help guiding the dosage to improve clinical outcome. Other approaches for optimizing thiopurine therapy in IBD include combination therapy with allopurinol, 5-aminosalicylates, and/or biologics. Similar strategies are yet to be proven effective in improving the outcome of MTX therapy. Important challenges for the management of IBD in the future relate to individualized dosing of immunomodulators for maximal efficacy with minimal risk of side effects. As low-cost conventional immunomodulators still remain a mainstay in pharmacotherapy of IBD, more research remains warranted, especially to substantiate these tailored management strategies in controlled clinical trials.

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

“…The metabolite 6-MMP has been related to thiopurine-induced liver toxicity [68]. Metabolism of 6-MP by the anabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) eventually leads to the pharmacologically active 6-thioguanine nucleotide (6-TGN) [69]. The low bioavailability (5-37%) of 6-MP is a result of the high first-pass effect caused by the rapid and extensive metabolism of XO into inactive metabolites [70].…”

Genotypes Affecting the Pharmacokinetics of Anticancer Drugs

“…6-Mercaptopurine (6-MP) is an analog of guanine and hypoxanthine, which is widely used in the treatment of patients with inflammatory bowel disease and patients with acute lymphoblastic leukemia [71, 72]. The principal cytotoxic and immunosuppressive effects of thiopurine drugs are caused by incorporation of thioguanine nucleotides into DNA or RNA (Fig.…”

“…Therefore, TPMT plays a pivotal role in the production of active thiopurine metabolites by diverting a proportion of available substrates away from the anabolic pathway of thiopurines to generate methylated metabolites. To date, more than 35 variants in the gene encoding TPMT have been associated with decreased TPMT activity [72]. Three variants TPMT*2, TMPT*3A, and TMPT*3C account for 80–85 % of intermediate or low enzyme activity in the Caucasian population [5].…”

“…Individuals who are heterozygous carriers or homozygous for an inherited functional mutation in TPMT have an increased risk of developing life-threatening myelosuppressive effects of thiopurines. Patients who are heterozygous for a TPMT deficiency require a lower dose of thiopurines (30–50 % of the regular dose) and substantial reduced doses (>tenfold) or the use of alternative agents is recommended in patients homozygous for a TPMT deficiency [72, 73]. Upfront screening of patients for variants in TPMT , followed by a dose reduction in heterozygous or homozygous carriers of a variant, reduced hematological events during thiopurine treatment of inflammatory bowel disease [74].…”

“…The maximum concentration of 6-MP in plasma is observed approximately 1.3 h after oral administration of 6-MP and the elimination half-life is approximately 1.8 h [76]. One approach to ensure optimal dosing of thiopurines is to monitor the thiopurine metabolites in erythrocytes [72]. A population pharmacokinetic model has been developed to predict the concentrations of thioguanine nucleotides in erythrocytes in pediatric patients with acute lymphoblastic leukemia and the most influential covariate examined proved to be the TMPT genotype [77].…”