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

Abstract

Summary. A spectropliotometric method was used to show that azathioprine ("Iinuran",) is converted into 6-mercaptopiirine hy a second-order reaction with glutatliione. In the pH ranne studied (6-85-8-45), at 37° in 50 niM phosphate, the rate of formation of 6-mt*rcaptopiirine is given hy the expression: d[6-merc:iptopurine]/dt " 0 32 (pH -6R) [azatlitoprine] [gKitathione] mole .sec.-* litre-'. The results were applicahle to U»e formation of 6-mercaptopurine from azathioprine and gliitathionc iu plasma. The half-time for conversion of azathioprine into 6-nu'rcaptopurine at pH 7-35 and 37° in the presence of 1 mM glutatliione was 47 min.At pH values ahove 10 formation of 5-niercapta-l-methyl-4-nitroiniidazole from azathioprine was ohser\'ed in vitro. The mercaptoimidazole was detected in the nrine of patients after oral doses of azathioprim-. A spectrophotonietric a.ssay after fractionation on Sephadex G-15 was used to follow the time-course of excretion of the iniid;r/t)l('.Net conversion of aziithioprine into 6-thiouric acid after treatment with azathioprine wa.'i followed hy a spectrophotonietric assay in\olving co-prccipitation of urinar>' 6-thiouric acid with uric acid. Tlie tiuie-cour.sc of urinary 6-thiouric acid excretion was similar to that of the mercsiptoimidazolc. and is consistent with the rates of azathioprine cleavage observed in vivo. These metabolites were mainly excreted within H hr. of an oral dose of azathioprine.The relevance of these results to the action of aziithioprim' and to improvemeuts in control of its clinical use are discussed.

Hyperglycemic, Hyperosmolar, Nonketoacidotic Diabetes: A Complication of Steroid and Immunosuppressive Therapy

“…Azathioprine's initial metabolic product in the body, 6-mercaptoparine, 37 decreases the uptake and oxidation of glucose by sarcoma tissue but net normal tissue. 38 However, since there is evidence that its biologic action is not due only to conversion to 6-mercaptopurine, 37 studies with the latter drug may not be representative. Inhibition of the synthesis of either insulin or the enzyme(s) which regulate glucose utilization might be expected due to its effects on RNA-dependent protein synthesis.…”

Effects of azathioprine on the human mixed lymphocyte reaction (MLR).

“…This difference in activity was decreased partially in the presence of thiol groups of reduced glutathione and red blood cells which are known to split azathioprine to 6-MP (Chalmers et al, 1967;Miranda et al, 1973;Maddocks, 1979).…”

“…5-Mercapto-1-methyl-4-nitroimidazole was synthesised and checked for purity as described by Chalmers et al (1967). It was dissolved in PBS.…”

HPLC Determination of 6-Thiouric Acid and 6-Mercaptopurine in Organ Transplant Patient Serum

“…The first analytic attempts were spectrophotometric assays of 6TU that showed poor sensitivity (12)(13)(14), with detection limits of 10 ug/ml in plasma and 1 ug/ml to 50 u g h 1 in urine. VanScoik et a1 (15) developed a high performance liquid chromatographic (HPLC) assay with a detection limit of 12.5 ng of 6TU/ml of plasma.…”