title: Monitoring of azathioprine treatment by determination of 6-thioguanine nucleotide concentrations in erythrocytes.
abstract: Thioguanine nucleotides (6-TGN) are intracellular metabolites that may contribute to the antiproliferative effects of AZA. The objectives of our study were to describe the variability of 6-TGN concentrations during AZA therapy and to investigate possible correlations between 6-TGN levels and subsequent myelosuppression. We measured 6-TGN concentrations in RBC of 65 renal transplant recipients from day 0 until 11-64 days after transplantation. High 6-TGN concentrations were observed in relation to elevated S-creatinine. In 15 patients, 6-TGN concentrations above 200 pmol/8 x 10(8) RBCs were measured (high 6-TGN group: mean maximal 6-TGN = 552 pmol/8 x 10(8) RBCs, SE = 91). In the remaining 50 patients, mean maximal 6-TGN was 82 pmol/8 x 10(8) RBCs, SE = 6.1 (low t-TGN group). In the former group, mean S-creatinine measured on the day of maximal 6-TGN was 466 mumol/L (SE = 62.3), while in the latter it was 190 (SE = 14.7). In the high 6-TGN group, we observed a lower mean nadir neutrophil count than in the low 6-TGN group (3.4 vs. 5.1 x 10(9) neutrophils/L). The nadir neutrophil count occurred, on the average, 12.7 days after maximal 6-TGN in the high 6-TGN group, with no such delay in the low 6-TGN group. This study demonstrates for the first time that 6-TGN in RBCs may rise to very high levels during impaired renal function. Furthermore, the results support the hypothesis that myelosuppressive side effects of AZA therapy correlate with 6-TGN concentrations. Renal transplant recipients may benefit from the monitoring of AZA through RBC 6-TGN measurements.
authors.affiliation: Department of Clinical Pharmacology, University of Oslo, National Hospital-Rikshospitalet, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Bergan
authors.forename: H E
authors.initials: HE
authors.lastname: Rugstad
authors.forename: O
authors.initials: O
authors.lastname: Bentdal
authors.forename: O
authors.initials: O
authors.lastname: Stokke
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000627:therapeutic use*; D002648:Child; D003404:Creatinine / Q000097:blood; D016903:Drug Monitoring; D004912:Erythrocytes / Q000737:chemistry*; D005260:Female; D006084:Graft Rejection / Q000097:blood* / Q000188:drug therapy*; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D013873:Thionucleotides / Q000097:blood*
chemical_list: D006150:Guanine Nucleotides; D013873:Thionucleotides; C003964:6-thioguanylic acid; D003404:Creatinine; D001379:Azathioprine