Biotransformation of 6-thioguanine in inflammatory bowel disease patients: a comparison of oral and intravenous administration of 6-thioguanine.

BACKGROUND AND PURPOSE: Although 6-mercaptopurine and azathioprine are effective treatments in inflammatory bowel disease (IBD), many patients discontinue treatment because of side effects. 6-Thioguanine (6-TG) may be an alternative rescue therapy in these intolerant patients but the pharmacokinetics of 6-TG are not fully described. Here we have measured the pharmacokinetics of the biotransformation of 6-TG into the pharmacologically active metabolites, 6-thioguanine nucleotides (6-TGN), in IBD patients. EXPERIMENTAL APPROACH: In 12 patients with IBD, levels of 6-TGN and activities of thiopurine S-methyltransferase, xanthine oxidase and hypoxanthine guanine-phosphoribosyl-transferase were measured in a two-stage (i.v. and p.o. administration of 0.3 mg·kg(-1) 6-TG), prospective study. Median exposure of 6-TGN in red blood cells (RBC) was expressed as the ratio of the area under the curve (AUC) per mg 6-TG after i.v. dosing and that after p.o. dosing. KEY RESULTS: The median AUC per mg 6-TG was 1068 (p.o.) and 7184 (i.v.) pmol·h (8 × 10(8) RBC)(-1) . Median exposure of 6-TGN in RBC was 15% (9-28). Hypoxanthine guanine-phosphoribosyl-transferase activity correlated with peak 6-TGN and with AUC per mg (r= 0.7, P= 0.02 and r= 0.6, P= 0.03 respectively). Thiopurine S-methyltransferase activity was inversely related to AUC per mg (r=-0.8, P= 0.001), whereas that of xanthine oxidase was correlated with a lower peak 6-TGN (r=-0.7, P= 0.02). CONCLUSIONS AND IMPLICATIONS: The great variability of the AUC per mg for 6-TG observed after p.o. and i.v. administration of 6-TG, was partly explained by variability in activities of metabolizing enzymes. Exposure of 6-TGN was low in all patients.

Correlation between Saccharomyces cerevisiae DNA in intestinal mucosal samples and anti-Saccharomyces cerevisiae antibodies in serum of patients with IBD.

AIM: To investigate the correlation between ASCA and presence of mucosal S. cerevisiae DNA in a population of CD, ulcerative colitis (UC) patients and controls. METHODS: S. cerevisiae-specific primers and a fluorescent probe were designed for a 5' exonuclease real time PCR (TaqMan) assay, which is a homogenous system using a fluorescent-labelled probe for the detection of PCR product in real time. We analyzed the relation of the PCR results with the ASCA findings in a group of 76 inflammatory bowel disease (IBD) patients (31 CD, 45 UC) and 22 healthy controls (HC). RESULTS: ASCA (IgA or IgG) were positive in 19 (61%) patients with CD, 12 (27%) with UC and none of the HC. PCR amplification was inhibited and excluded from the final results in 10 (22%) UC patients, 7 (22%) CD patients, and 6 (30%) HC. In only 15 of the mucosal samples, S. cerevisiae DNA was detected by real time PCR, including 7 (29%) in CD, 7 (19%) in UC, 1 (6%) in HC. In 4 CD and in 4 UC patients, ASCA and mucosal S. cerevisiae were positive. Mucosal S. cerevisiae was present in combination with negative ASCA IgA and IgG in 3 UC, and 3 CD patients. CONCLUSION: We conclude that since the presence of S. cerevisiae in colonic mucosal biopsy specimens is very rare, ASCA is unlikely to be explained by continuous exposure to S. cerevisiae in the mucosa. Therefore, ASCA formation must occur earlier in life and levels remain relatively stable thereafter in immunological susceptible persons.