Large interindividual variability in bioavailability of azathioprine in renal transplant recipients

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Abstract
Azathioprine (Aza), one of the first immunosuppressive agents that proved successful in clinical transplantation, is still widely used. The drug is given in standardized doses which are adjusted only when signs of myelotoxicity occur. It has only recently become possible to specifically determine the level of Aza in plasma. In this study the plasma concentrations of Aza and its primary metabolite 6‐mercaptopurine (6‐MP) were measured after an oral and an equally large intravenous dose of Aza had been administered to 6 recipients of cadaveric renal allografts. The bioavailability of Aza was low and highly variable (range 5.1‐23.7%). The maximum plasma peak concentration of 6‐MP after an i.v. dose of Aza was 17% of the maximum plasma Aza concentration, but after oral intake the peak concentrations of Aza and 6‐MP were in the same range (38±50 ng/ml and 38±45 ng/ml, respectively). The time to peak, peak concentrations, clearance and elimination half‐life varied widely between patients. It is concluded that the pharmacokinetics of Aza showed remarkably large interindividual variability. Therefore, it is possible that the immunosuppressive potency of Aza would be improved if the drug were dosed according to the individual pharmacokinetics rather than according to the standardized dosing schedules currently used in organ transplantation.