Serum azathioprine and 6-mercaptopurine levels and immunosuppressive activity after azathioprine in uremic patients.

The pharmacokinetics of azathioprine (AZA) and 6-mercaptopurine (6-MP) was studied in uremic patients after 100 mg AZA intravenously (fifteen patients) and orally (eight patients). 6-MP was analysed with gas chromatography mass spectrometry following extractive alkylation. AZA was determined indirectly assuming quantitative conversion to 6-MP in whole blood. The plasma concentration of AZA fell rapidly after i.v. administration. The mean half-time of elimination for the first rapid phase (t1/2 alpha) was 6.1 min (S.D. +/- 4.1) and for the terminal phase (t1/2 beta) 50 min (+/- 31). The total plasma clearance (Cl) was 6.9 1./min (+/- 3.0). AZA was rapidly converted to 6-MP in vivo, and maximal plasma concentrations of 6-MP were found as early as 5 min after i.v. injection of AZA. The mean t1/2 alpha was 4.6 min (+/- 2.2), t1/2 beta 74 min (+/- 58) and Cl 8.0 1./min (+/- 5.8). The plasma levels of both AZA and 6-MP were either low or undetectable 4-6 h after dose. In erythrocytes AZA levels were low or undetectable indicating rapid conversion to 6-MP in these cells. 6-MP concentration - time curve in erythrocytes was similar to that in plasma, except for a somewhat slower terminal phase of elimination. Oral administration of AZA generated flat plasma curves for AZA and 6-MP. The area under the concentration - time curve (AUC) was considerably smaller than after i.v. administration, 18 and 41% for AZA and 6-MP, respectively. There seems to be little danger of accumulation of AZA/6-MP in uremia. We also studied inhibition of Leucoagglutin (LA) stimulated lymphocyte proliferation by patient plasma at different times in six of the patients following AZA i.v. Sera drawn at 5, 10 and 30 min significantly inhibited the LA-induced proliferation, with an estimated minimum effective concentration of 6-MP in the cultures of about 0.02-0.04 microM. This suggests the possibility of a therapeutic effect even of the low plasma levels of 6-MP obtained after AZA orally. The combined use of sensitive pharmacokinetic and immunological assays as described should be useful in studying the relationship between plasma levels of AZA/6-MP and their immunosuppressive effect and toxicity.