IMMUNOSUPPRESSIVE METABOLITES OF CYCLOSPORINE IN THE BLOOD OF RENAL ALLOGRAFT RECIPIENTS

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Abstract
Cyclosporine levels by radioimmunoassy (RIA) and high-performance liquid chromatography (HPLC) were monitored in serial blood samples (n=177) from 11 renal allograft recipients. HPLC analysis revealed three parimary metabolities of CsA (M17, and M21) in peak and trough blood samples; M17 was the preponderant metabolite. In 4 patients on whom serial metabolite assays were performed, M17 was found in the blood at 86–2004 ng/ml; M1 and M21 were found at up to 100 ng/ml. The immunosupressive properties of purified metabolities M1, M17, M21, and M8 (which was not detected in the blood) were compared with CsA. M17—and, to a lesser extetent, M1 and M21—were found to inhibit the in vitro response of human mononuclear cells in the mixed leukocyte culture and in mitogen (phytohemagglutinin [PHA], eoncanavalin A [Con A], and pokeweed mitogen [PWM]) assays at 1000 ng/ml. M8 exhibited no in vitro inhibitory activity. M17 was further tested at 10–1000 ng/ml in PHA and mixed lymphocyte culture (MLC) assays. M17 had considerably less inhibitory activity (12–43%) than CsA (18–70%) in the PHA assay. However, in MLC experiments M17 blocked the proliferative response by 39–72% at 100–800 ng/ml, which appoached the degree of inhibition exhibited by CsA (63–87%). In 34 of 37 (92%) patient blood samples, the level of metabolite M17 was found to exceed the parent drug leve and could not be measured accurately by RIA. The observed in vitro immunosuppressive activity of metabolities (particularly M17) and their presence in the blood of renal allograft recipients suggest a possible role for thes emetabolities in the immunopharmacology of CsA.