Cyclosporine measurement by FPIA, PC-RIA, and HPLC following liver transplantation

The factors affecting CyA dosing and kinetics in LT patients are complex, and have been thoroughly investigated and reviewed. Plasma or WB CyA concentration monitoring remains the best method presently available for adjusting CyA dosage in LT patients in a timely manner. The availability of an FPIA assay for CyA has produced rapid drug analysis for transplant patient monitoring, but adds additional factors that must be considered in interpreting CyA concentrations. Liver dysfunction may disproportionately elevate CyA plasma or blood levels when analyzed by FPIA in relation to PC-RIA or HPLC, and adjustment of the therapeutic range or analysis by a more specific assay method may be necessary for dosage adjustment in these patients. The availability of a more specific antibody in an FPIA assay may avert these problems, as would the development of immunologic monitoring techniques that provide a global assessment of immune suppression produced by increasingly complex immunosuppressive regimens in LT patients

Impaired clearance of ceftizoxime and cefotaxime after orthotopic liver transplantation.

The pharmacokinetics of ceftizoxime (CZX) and of cefotaxime (CTX) were studied in five children and five adults after orthotopic liver transplantation (OLT). Delayed clearance of CZX (clearance of 0.21 to 1.26 ml/min per kg [body weight]) and CTX (clearance of 0.40 to 1.49 ml/min per kg) occurred in 7 of the 10 OLT patients. We conclude that abnormal CZX and CTX clearance is common after OLT and may be associated with minimal change in serum creatinine

Isolation of 10 cyclosporine metabolites from human bile

Ten metabolites of cyclosporine were isolated from the ethyl ether extract of bile from four liver transplant patients receiving cyclosporine. Two of the metabolites were unique and previously unidentified. Liquid-liquid partitioning into diethyl ether with subsequent defatting with n-hexane was used for the initial extraction form bile. Separation of the individual metabolites (A-J) was performed using a Sephadex LH-20 column and a gradient high performance liquid chromatographic method. The molecular weights of the isolated metabolites were determined by fast atom bombardment/mass spectrometry. Gas chromatography with mass spectrometic amino acid analysis was also used to identify the amino acid composition and the hydroxylation position of metabolites A, B, C, D, and G. Proton nuclear magnetic resonance spectra were utilized to disinguish the chemical shifts of N-CH3 singlets and NH doublets of metabolites A, B, C, and D. Metabolites A, E, F, H, I, and J were reported previously in human urine and animal bile. Metabolites C and D are dihydroxylated compounds which cannot be clearly described as previously isolated compounds. Metabolites B and G are novel metabolites with a mass fragment which corresponded to a loss of 131 Da from the protonated molecular ion (MH+) in the fast atom bombardment/mass spectrometry, suggesting that the double bond in amino acid 1 has been modified. Metabolites B and G were primarily isolated from the bile of one of the liver transplant patients which contained abnormally high concentrations of these two metabolites. The method described is an efficient procedure for isolating milligram quantities of the major metabolites with greater than 95% purity