The mixed lymphocyte reaction of Lesch-Nyhan patients (HGPRT deficient) was used to study the immunosuppressive effects of azathioprine and 6-mercaptopurine (6-MP). Mitogen stimulated lymphocytes of these patients are highly resistant to azathioprine and 6-MP. When both stimulator and responder lymphocytes in the MLR were HGPRT deficient, azathioprine (36 ,uM) was much more inhibitory than 6-MP (100 ,uM). Azathioprine produced inhibition of 98.2% and 78.5% compared with the values of 63.9% and 30.6% for 6-MP. The difference in inhibitory activity between azathioprine and 6-MP was reduced when normal stimulator lymphocytes were cultured with HGPRT deficient responder lymphocytes in the MLR. These results provide very strong evidence that the nucleotide metabolites of azathioprine and 6-MP are unnecessary for immunosuppression. They also suggest that azathioprine and 6-MP interfere with antigenic triggering of the MLR.

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1. A fluorimetric method has been developed for measuring therapeutic concentrations of 6‐thioguanine in human plasma. The drug was measured as an oxidized derivative, guanine 6‐sulphonate. 2. 6‐thioguanine was extracted from plasma by a novel procedure which isolated the drug from an interfering plasma components. This method involved the formation of the thioguanine phenyl mercury derivative in alkaline plasma and its extraction into toluene. The free drug was released by back‐extraction into hydrochloric acid. 3. The assay is specific and shows a limit of sensitivity of 5 ng/ml. This was shown to be adequate for measuring plasma concentrations of 6‐thioguanine after the administration of a 160 mg dose in a patient with leukaemia.

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