Determination of 6-Thioguanine and 6-Methylmercaptopurine Metabolites in Renal Transplantation Recipients and Patients With Glomerulonephritis Treated With Azathioprine

Abstract

The metabolism of azathioprine (AZA) was studied by monitoring the concentrations of red blood cell (RBC) 6-thioguanine nucleotides (6-TGN) and of 6-methylmercaptopurine metabolites (6-mMP) in 27 renal transplantation recipients and in 10 patient subjects with glomerulonephritis (GN). Concentrations of 6-TGNs and 6-mMP metabolites were measured using high-performance liquid chromatography (HPLC). Six patients from the group of renal transplantation recipients were also administered allopurinol. Median values of RBC 6-TGN and of 6-mMP metabolites concentrations in 21 renal transplantation recipients (without allopurinol) were 122 pmol/8x10(8) RBCs (range, <60-298) and 280 pmol/8x10(8) RBC (range, <150-1330), respectively; there was no correlation between concentrations of 6-TGN and of 6-mMP metabolites. The group of 21 renal transplantation recipients received different AZA doses (100 or 50 mg/d) related to clinical symptoms of AZA intolerance. The median values of 6-TGN concentrations in these subgroups were 131 and 122 pmol/8x10(8) RBCs and were not significantly different. Median values of 6-TGN concentrations in patients given allopurinol were significantly higher, despite AZA dose reduction, compared with the group without allopurinol and were equal to 363 and 122 pmol/8x10(8) RBC, p < 0.004, respectively. No significant differences were found between the concentrations of 6-mMP metabolites in either group. In the group of renal transplantation recipients, a significant correlation between white blood cell (WBC) count and 6-TGN concentration was established (r(s) = -0.59, p < 0.005). In the group of GN patients, the median values of 6-TGN and of 6-mMP metabolites concentrations were 108 pmol/8x10(8) RBCs (range, 0-297) and 420 pmol/8x10(8) RBC (range, 0-1440), respectively. There were no significant correlations between either the WBC count and 6-TGN concentrations or between 6-TGN concentrations and 6-mMP metabolites. We expect the results of our study to provide indications for better individualization of AZA therapy.

Influence of xanthine oxidase on thiopurine metabolism in Crohn’s disease

“…Hepatotoxicity following AZA dose escalation has been shown to occur in about one in four patients treated with AZA and frequently leads to the withdrawal of therapy 41 . Concomitant allopurinol therapy with reduced dose of AZA improves clinical response by increasing 6TGNs and by‐passes AZA‐induced hepatoxicity 21, 22, 24 . Our results demonstrated that allopurinol co‐therapy with AZA reduced 6TU excretion below detection levels.…”

“…Prescription of normal doses of AZA for a patient receiving allopurinol can lead to severe myelotoxicity 20 . However, allopurinol has been deliberately combined with low‐dose AZA in an attempt to improve AZA efficacy 21–24 …”

The role of thiopurine metabolites in inflammatory bowel disease and rheumatological disorders

“…A therapeutic benefit for a combination of low-dose allopurinol and thiopurines was first demonstrated in renal transplantation, where the addition of allopurinol improved graft survival 44 and also increased 6TGN levels. 45 In 2005, the efficacy of combination therapy was first demonstrated in a group of 15 patients with clinically active IBD, who were documented thiopurine shunters (mean 6TGN = 186, mean 6MMP = 10 380). With the addition of 100 mg allopurinol and a dose reduction of AZA to 25-50% of the original thiopurine dose, this adverse metabolic profile was reversed with mean 6TGN increasing to 385 and mean 6MMP decreasing to 1732 (P < 0.001).…”

The Pharmacogenetic Basis of Individual Variation in Thiopurine Metabolism

“…This strategy was therefore abandoned and allopurinol instead found its niche in the treatment of gout [1]. In 1993 it was reported that coprescription of AZA and allopurinol improved renal graft survival and optimized thiopurine metabolite profiles [102,103]. More recently interest in combination treatment using low-dose AZA/MP and allopurinol in IBD has focused on bypassing thiopurine hyper methylation.…”