Cyclosporine metabolites: are they active?

Knowledge about CsA metabolites is critical to our understanding and application of therapeutic drug monitoring to guide most-effective dosing of CsA in continuing efforts to minimize the risks of side effects while maximizing the opportunity for immunosuppression (1-3). This controversial issue has been the subject of many studies published in this and other journals and a topic of keen interest to many in the transplant field. In this issue of Clinical Chemistry, Copeland and colleagues report their investigation of the in vitro immunosuppressive activity of CsA metabolites they purified from urine of renal-transplant patients (4). A singularly important characteristic of this work is that they used well-characterized purified metabolites-essential in attempts to attribute immunosuppressive activity to a specific metabolite. Bowers et al. (5) emphasized the importance of using well-characterized pure metabolites in their recent investigations in which they also isolated a metabolite, which co-eluted with metabolite 17 in HPLC chromatograms, and identified it as hydroxydesmethyl-cyclosporine. The other noteworthy point about the experimental design in the study of Copeland et al. is the use of three different types of in vitro tests of immunosuppression. Although in previous reports of studies of the in vitro immunosuppressive activity of CsA metabolites it was not possible for all investigators to use both well-characterized metabolites and the three types of immunosuppression tests used by Copeland and coworkers, it is interesting to note that the main conclusions drawn regarding the immunosuppressive activity of some metabolites relative to CsA, especially metabolite 17, are in accord with those of most of the other studies. One of the conclusions of the Copeland group is that, except for metabolites 17 and 1 in one of the test systems (the secondary MLC), the immunosuppression relative to that of CsA for the studied metabolites was less than 1O%-a conclusion that is in harmony with many but not all previous studies of this problem. Although one cannot extrapolate directly from in vitro tests to the in vivo circumstances of transplant patients, the authors make the reasonable suggestion that, in transplant patients with relatively stable metabolite/parent-drug concentrations, measuring M17 (16% of the activity of CsA in the secondary MLC and present in blood and tissues in relatively high