Acute-phase response, interleukin-6, and alteration of cyclosporine pharmacokinetics

OBJECTIVE: Administration of interleukin-6 partially reproduces the inhibitory effects of the acute-phase response on cytochrome P450-dependent drug metabolism. The aim of the study was to determine whether endogenous cytokine has such an effect in patients treated by cyclosporine, which is metabolized by the cytochrome P4503A subfamily. METHODS: Blood cyclosporine and serum interleukin-6 levels were determined in six patients undergoing bone marrow transplantation, as long as they received cyclosporine by continuous infusion. Two serum acute-phase proteins, C-reactive protein and alpha 1-acid glycoprotein, and two cyclosporine metabolites, AM1 and AM9, were also determined. RESULTS: At the time of marrow infusion, levels of specific markers of inflammation were low. A peak in interleukin-6 level was then observed a mean of 10.8 days after transplantation, closely associated with variations in C-reactive protein levels. A parallel twofold increase in AM1 concentrations was observed, followed by a three-fold increase in cyclosporine levels, which peaked 4.8 days after interleukin-6. The times of peak cyclosporine and AM1 levels correlated with the time of peak interleukin-6 levels. AM9 was detectable in three patients but concentrations fell when interleukin 6 became detectable. CONCLUSIONS: An inflammatory reaction could be an important source of intraindividual variability in cyclosporine pharmacokinetics, possibly through an inhibition of cytochrome P4503A-dependent enzyme activities by endogenous interleukin-6. Blood AM1 accumulation might be explained by a secondary metabolic step that is highly sensitive to the inhibitory effect of interleukin-6.