The determination of metabolite M17 and its meaning for immunosuppressive cyclosporin therapy.
Cyclosporin A (CyA) is intensively metabolized by the hepatic cytochrome p450 III monooxygenase A system in the human liver, the most important metabolites being M1, M17, and M21. Because CyA and its metabolites have nephrotoxic, hepatotoxic, and neurotoxic side effects, CyA dosage must be calculated to avoid the risk of organ rejection through underdosage and toxic organ damage through overdosage or accumulation of metabolites. In this study, we determined the whole-blood concentrations of cyclosporin and metabolite M17 by high-pressure liquid chromatography (HPLC) and by monoclonal specific and polyclonal nonspecific fluorescence polarization immunoassay (Abbott) in patients after immunosuppressive treatment. Patients with different resorption and metabolization rates showed high individual variations. CyA concentrations in patients with good liver function and low concentrations of CyA metabolites showed a good correlation between the HPLC and the FPIA (TDx-monoclonal assay) methods in ranges between 25 and 180 ng/mL. TDx-monoclonal was not always as precise as HPLC. In cases of metabolic disorders, we found false high CyA concentrations assayed with the immunologic method, caused by a crossreaction of the elevated metabolite concentration. We found that HPLC rendered more information about the extent of immunosuppressive activity and the metabolization rate and showed a good correlation with the concentration of metabolite M17 and total metabolites measured with the Abbott CyA polyclonal kit.
Khoschsorur
G
G
Department of Surgery and Clinical Laboratory, University of Graz, Austria.
Auer
T
T
Lanzer
G
G
Petritsch
P
P
Holzer
H
H
Tscheliessnigg
K H
KH
D000906:Antibodies; D000911:Antibodies, Monoclonal; D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy; D016026:Bone Marrow Transplantation; D002851:Chromatography, High Pressure Liquid; D003429:Cross Reactions; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D003524:Cyclosporins / Q000009:adverse effects / Q000097:blood*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D016231:Fluorescence Polarization Immunoassay; D006084:Graft Rejection / Q000517:prevention & control; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects; D016030:Kidney Transplantation; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D016031:Liver Transplantation; D008657:Metabolic Clearance Rate; D009420:Nervous System / Q000187:drug effects; D012307:Risk Factors
D000906:Antibodies; D000911:Antibodies, Monoclonal; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C051527:cyclosporine metabolite M17; D003577:Cytochrome P-450 Enzyme System