Pharmacokinetics of 6-Thioguanine in Patients With Inflammatory Bowel Disease

Abstract

6-Thioguanine (6-TG) seems to be an attractive alternative in both AZA- and 6-MP-intolerant and -resistant IBD populations. However, little is known of 6-TG pharmacokinetics, metabolite levels, and their correlation with drug efficacy and toxicity in IBD patients. This study reports the 6-TG pharmacokinetics in a population of IBD patients and the predictive value of metabolite concentrations. Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) concentrations were measured in 28 IBD patients at t = 1, 2, 4, and 8 weeks after starting 6-TG, 20 mg once daily. Outcome measures included mean 6-TGN concentrations (+/-95% confidence interval [CI95%]) and their associations with TPMT genotype, 6-TG dose, and hematological, hepatic, pancreatic, and efficacy parameters during the 8 week period. Steady-state 6-TGN concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days, and measured 856 (CI95% 715-997) pmol/8 x 10 RBCs. Large interpatient variability occurred at all time-points. No correlation was found between steady-state 6-TGN concentrations and drug dose per kilogram body weight. No significant differences in 6-TGN concentrations were found between patients with adverse events and patients without any event. Also, mean 6-TGN concentrations did not differ in patients with active disease versus patients in remission. In IBD patients on 6-TG treatment, large interindividual differences in metabolite concentrations occur. In our population, we could not demonstrate a clear relationship between 6-TGN concentrations on one hand and toxicity and efficacy on the other, as exist in AZA- and 6-MP-treated patients.

Analysis of Thiopurine S-Methyltransferase Genotypes in Japanese Patients with Inflammatory Bowel Disease

“…TPMT activity is reported to depend on the genetic polymorphism of high-versus lowmetabolizing alleles (5,6) (13). In this study, we found TPMT*3C mutation in 0.9% of the Japanese population, and this is similar to the observations by Kubota et al (11,14).…”

“…6-TUA is an inactive metabolite, and 6-MMP is associated with hepatotoxicity but therapeutically inactive (7). The cytotoxic and immunosuppressive properties of AZA/6-MP are mediated by 6-TGNs, which are incorporated into the DNA, thus leading to DNA breakage and the inhibition of immune cell proliferation (5 …”

“…AZA and 6-MP are metabolized to 6-thiouric acids (6-TUAs ) , , and 6-thioguanine nucleotide (5,6). 6-TUA is an inactive metabolite, and 6-MMP is associated with hepatotoxicity but therapeutically inactive (7).…”

Thiopurines in inflammatory bowel disease: New strategies for optimization of pharmacotherapy?

“…We found that 6-TGN concentrations showed large interpatient variability, similar to pharmacokinetic data in leukemic populations on 6-TG [56,57]. 6-TG derived 6-TGN concentrations reached steady state after 4 weeks, similar to AZA or 6-MP derived 6-TGN concentrations [22,58]. At steady state there was a 5-fold range in steady state 6-TGN concentrations, which is substantial but less pronounced than the range in 6-TGN originating from AZA or 6-MP [22,58].…”

“…6-TG derived 6-TGN concentrations reached steady state after 4 weeks, similar to AZA or 6-MP derived 6-TGN concentrations [22,58]. At steady state there was a 5-fold range in steady state 6-TGN concentrations, which is substantial but less pronounced than the range in 6-TGN originating from AZA or 6-MP [22,58]. Beforehand, we expected a lesser variation in steady state 6-TGN levels as 6-TGN derived from 6-TG are formed in one single step compared to multiple steps when originating from AZA and 6-MP.…”