Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease

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 patient

Pharmacokinetics of 6-mercaptopurine in patients with inflammatory bowel disease: implications for therapy

Proper prospective pharmacokinetic studies of 6-mercaptopurine (6-MP) in inflammatory bowel disease (IBD) patients are lacking. As a result, conflicting recommendations have been made for metabolite monitoring in routine practice. The authors have evaluated 6-MP pharmacokinetics in IBD patients, including the genetic background for thiopurine methyltransferase (TPMT). Red blood cell (RBC) 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine ribonucleotide (6-MMPR) concentrations were measured in 30 IBD patients at 1, 2, 4, and 8 weeks after starting 6-MP, 50 mg once daily. Outcome measures included mean 6-TGN and 6-MMPR concentrations (+/- 95% confidence interval, CI95%) and their associations with TPMT genotype, 6-MP dose, and hematologic, hepatic, pancreatic, and efficacy parameters during the 8-week period. Steady-state concentrations were reached after 4 weeks, indicating a half-life of approximately 5 days for both 6-TGN and 6-MMPR; the concentrations were 368 (CI95% 284-452) and 2837 (CI95% 2101-3573) pmol/8 x 10 RBCs, respectively. Large interpatient variability occurred at all time points. TPMT genotype correlated with 6-TGN concentrations (0.576, P < 0.01), and patients with mutant alleles had a relative risk (RR) of 12.0 (CI95% 1.7-92.3) of developing leukopenia. A 6-MMPR/6-TGN ratio less than 11 was associated with therapeutic efficacy. Based on this pharmacokinetic analysis, therapeutic drug monitoring is essential for rational 6-MP dosin

Red meat intake-induced increases in fecal water genotoxicity correlate with pro-carcinogenic gene expression changes in the human colon

Red meat consumption is associated with an increased colorectal cancer (CRC) risk, which may be due to an increased endogenous formation of genotoxic N-nitroso compounds (NOCs). To assess the impact of red meat consumption on potential risk factors of CRC, we investigated the effect of a 7-day dietary red meat intervention in human subjects on endogenous NOC formation and fecal water genotoxicity in relation to genome-wide transcriptomic changes induced in colonic tissue. The intervention showed no effect on fecal NOC excretion but fecal water genotoxicity significantly increased in response to red meat intake. Colonic inflammation caused by inflammatory bowel disease, which has been suggested to stimulate endogenous nitrosation, did not influence fecal NOC excretion or fecal water genotoxicity. Transcriptomic analyses revealed that genes significantly correlating with the increase in fecal water genotoxicity were involved in biological pathways indicative of genotoxic effects, including modifications in DNA damage repair, cell cycle, and apoptosis pathways. Moreover, WNT signaling and nucleosome remodeling pathways were modulated which are implicated in human CRC development. We conclude that the gene expression changes identified in this study corroborate the genotoxic potential of diets high in red meat and point towards a potentially increased CRC risk in humans

Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-Induced Leukopenia in Inflammatory Bowel Disease

BACKGROUND AND AIMS: Only a quarter of thiopurine-induced myelotoxicity in IBD patients is related to TPMT deficiency. We determined the predictive value of 6-thioguanine nucleotide (6TGN) and 6-methylmercaptopurine ribonucleotide (6MMPR) concentrations one week after initiation (T1) for development of leukopenia during the first eight weeks of thiopurine treatment. METHODS: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomised controlled TOPIC trial (ClinicalTrials.gov NCT00521950). Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts <3.0x10*(9)/L. For comparison, patients without leukopenia who completed the eight weeks on stable dose were selected from the first 272 patients of the TOPIC trial. RESULTS: Thirty-two patients with, and 162 patients, without leukopenia were analysed. T1 threshold 6TGN concentrations of 213 pmol/8x10*(8) erythrocytes and 3,525 pmol/8x10*(8) erythrocytes for 6MMPR were defined: patients exceeding these values were at increased leukopenia risk (OR 6.2 (95%CI: 2.8-13.8) and 5.9 (95%CI: 2.7-13.3), respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared to azathioprine (OR 7.3 (95%CI: 3.1-17.0)), and concurrent anti-TNF therapy (OR 5.1 (95%CI: 1.6-16.4)). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-TNF therapy revealed that elevations of both T1 6TGN and 6MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6MMPR or 6TGN threshold concentration (AUC 0.84 (95%CI: 0.76-0.92)). CONCLUSIONS: In approximately 80% of patients, leukopenia could be explained by T1 6TGN and/or 6MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice

The Prevalence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Thioguanine Is Not Associated with Clinically Significant Liver Disease

Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4-64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3-14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a higher mean corpuscular volume (P = 0.02), and a lower platelet or leukocyte count (P < 0.01 and P = 0.02, respectively) were associated with NRH. Three of the 7 patients with NRH did not have any associated clinical symptoms or signs. The other 4 had minor biochemical abnormalities only. Ultrasonography revealed splenomegaly in 3 of the 78 patients (4%; 95% confidence interval, 0%-9%), only one of whom had NRH. There was no clinically overt portal hypertension. The prevalence of NRH was 6% in liver biopsies obtained from IBD patients treated with thioguanine. Histopathological irregularities including NRH were not associated with clinically significant findings over the period of observatio