THE IMPORTANCE OF THIOPURINE METHYLTRANSFERASE ACTIVITY FOR THE USE OF AZATHIOPRINE IN TRANSPLANT RECIPIENTS1

The immunosuppressive efficacy of azathioprine is related to its rapid metabolism in vivo to 6-mercaptopurine (6MP), with subsequent conversion to thioguanine nucleotides by an anabolic route involving hypoxanthine-guanine phosphoribosyltransferase. Two alternative catabolic routes exist: oxidation to 6-thiouric acid via xanthine oxidase and methylation to 6-methylmercaptopurine via the enzyme thiopurine methyltransferase (TPMT). Catabolism via either route would restrict formation of the active metabolites.We analyzed TPMT activity in erythrocyte lysates of 25 controls, 25 uremic patients on dialysis, and 68 transplanted patients. Median activity was lower in controls (31.0 pmol/hr/mg Hb, range 16.2–43.0) and transplanted patients receiving only cyclosporine and prednisolone (31.7 pmol/hr/mg Hb, range 12.7–43.5) than in the azathioprine treated group, (36.1 pmol/hr/mg Hb, range 16.1–71.3), or the uremic group on dialysis, (35.5 pmol/hr/mg Hb, range 18.6–62.6) suggesting that both azathioprine and uremia induce the enzyme, but CsA does not.