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CONVERSION OF AZATHIOPRINE INTO MERCAPTOPURINE AND MERCAPTOIMIDAZOLE DERIVATIVES IN VITRO AND DURING IMMUNOSUPPRESSIVE THERAPY

1967; Wiley; Volume: 45; Issue: 6 Linguagem: Inglês

10.1038/icb.1967.68

1440-1711

AH Chalmers, PW Knight, MR Atkinson,

Adolescent and Pediatric Healthcare

Summary A spectrophotometric method was used to show that azathioprine (“Imuran”, BW 57–322) is converted into 6‐mercaptopurine by a second‐order reaction with glutathione. In the pH range studied (6·85·8·45), at 37° in 50 mM phosphate, the rate of formation of 6‐mercaptopurine is given by the expression: d[6‐mercaptopurine]/dt “0·32 (pH‐6·6) [azathioprine] [glutathione] mole sec. −1 litre −1 . The results were applicable to the formation of 6‐mercaptopurine from azathioprine and glutathione in plasma. The half‐time for conversion of azathioprine into 6‐mercaptopurine at pH 7·35 and 37° in the presence of 1 mM glutathione was 47 min. At pH values above 10 formation of 5‐mercapto‐1‐methyl‐4‐nitroimidazole from azathiopries was observed in vitro . The mercaptoimidazole was detected in the urine of patients after oral doses of azathioprine. A spectrophotometric assay after fractionation on Sephadex G‐15 was used to follow the time‐course of excretion of the imidazole. Net conversion of azathioprine into 6‐thiouric acid after treatment with azathioprine was followed by a spectrophotometric assay involving co‐precipitation of urinary 6‐thiouric acid with uric acid. The time‐course of urinary 6‐thiouric acid excretion was similar to that of the mercaptoimidazole, and is consistent with the rates of azathioprine cleavage observed in vivo . These metabolites were mainly excreted within 8 hr. of an oral dose of azathioprine. The relevance of these results to the action of azathioprine and to improvements in control of its clinical use are discussed.