ACUTE-PHASE RESPONSE, INTERLEUKIN-6, AND ALTERATION OF CYCLOSPORINE PHARMACOKINETICS

Objective: Administration of interleukin-6 partially reproduces the in hibitory effects of the acute-phase response on cytochrome P450-depend ent drug metabolism. The aim of the study was to determine whether end ogenous cytokine has such an effect in patients treated by cyclosporin e, which is metabolized by the cytochrome P4503A subfamily. Methods: B lood cyclosporine and serum interleukin-6 levels were determined in si x patients undergoing bone marrow transplantation, as long as they rec eived cyclosporine by continuous infusion, Two serum acute-phase prote ins, C-reactive protein and alpha(1)-acid glycoprotein, and two cyclos porine metabolites, AM1 and AM9, were also determined. Results: At the time of marrow infusion levels of specific markers of inflammation we re low. A peak in interleukin-6 level was then observed a mean of 10.8 days after transplantation, closely associated with variations in C-r eactive protein levels. A parallel twofold increase in AM1 concentrati ons was observed, followed by a three-fold increase in cyclosporine le vels, which peaked 4.8 days after interleukin-6. The times of peak cyc losporine 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 re action could be an important source of intraindividual variability in cyclosporine pharmacokinetics, possibly through an inhibition of cytoc hrome P4503A-dependent enzyme activities by endogenous interleukin-6. Blood AM1 accumulation might be explained by a secondary metabolic ste p that is highly sensitive to the inhibitory effect of interleukin-6.