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Measurement of AM19 and Other Cyclosporine Metabolites in the Blood of Liver Transplant Patients with Stable Liver Function

Summary Chronic renal impairment represents one of the major side effects of cyclosporine (CsA) immunotherapy for organ transplantation. The clinical relevance of selective measurement of CsA metabolites to correlating nephro-toxic activities remains inconclusive. A relatively simple and reliable method was developed to measure AM19 and four other CsA metabolites in whole blood by sequential solid-phase extraction and reversed phase high-pressure liquid chromatography (HPLC). The procedures were modified from a well-established method developed to quantitate CsA, the most important difference being in the elution step. The use of acetonitrile/methanol instead of ethylacetate/isopropanol in the etution procedure enhanced the absolute recoveries of metabolites. The washing steps were also slightly modified to recover AM19 quantitatively and specifically. Isocratic chromatographic conditions allowed very good separation of AM19, AM1, AM9, AM1c, AM4N, CsA, and the internal standard, cyclosporin C (CsC). Analytical recoveries for CsA and five of its metabolites ranged from 82 to 92%. No interfering substance from the matrix was found. The detection limit was 10 μg/l. The objectives of this study were to measure trough concentration of AM19 in whole blood, expressed as percentage of total metabolites plus parent CsA, and to determine if the blood level of AM19 could be used to predict subsequent changes in serum creatinine level in liver transplant patients. Twenty-three patients, who underwent liver transplantation between January and June 1993 were studied. Trough concentration of CsA in whole blood, serum creatinine and liver enzymes were constantly monitored. AM 19 level was determined 5–8 months after transplantation. Preliminary results suggest an inverse relationship between AM19 and serum creatinine levels. However, due to the limited number of patients available for the study, data from the present study are not conclusive with regard to whether the level of AM19 can be used to predict the development of irreversible renal impairment. Further studies with larger number of patients are required to address this issue.