Determination of cyclosporine and its metabolites in blood via HPLC-MS and correlation to clinically important parameters.
The narrow therapeutic window of the immunosuppressive drug cyclosporine (CsA), the interindividual variability of its metabolism, and the immunosuppressive activity/toxicity of some metabolites require investigation to correlate the parent substance and its metabolites and observed clinical parameters. Improved knowledge about these correlations may improve postoperative treatment of transplant patients. To observe such correlation therapeutic drug monitoring was performed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) on 202 blood samples of kidney transplant patients. As CsA and its metabolites are preferably bound to lipoproteins in vivo, sample preparation included protein precipitation, solid phase extraction, and separation on a reversed phase column. Mass-spectrometric detection by an electrospray ionization chamber made the detection and quantification of the sodium adducts of CsA and its metabolites AM1, AM1c, DihydroAM1, AM19, and AM4N possible. With the presented HPLC-MS method, rapid information was achieved about the specific metabolization in a patient. Statistical computations related CsA and its metabolite concentrations to clinically important blood parameters. Significant correlation to the blood level of bilirubin and liver enzymes confirmed the presumed hepatotoxic potential of CsA and some metabolites. Furthermore, a strong correlation of AM19 to CRP and IL6 was observerd. These parameters may influence the prognosis for atherosclerosis, inflammation, and chronic allograft nephropathy.
Vollenbroeker
B
B
Medizinische Klinik und Poliklinik D, Universitaetsklinikum Muenster, Muenster, Germany. b.vollenbroeker@uni-muenster.de
Koch
J-H
JH
Fobker
M
M
Suwelack
B
B
Hohage
H
H
Müller
U
U
D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000097:blood* / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D013058:Mass Spectrometry; D015203:Reproducibility of Results
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin