In vivo effects of interleukin-10 on human cytochrome P450 activity

Background: Injection of lipopolysaccharide into human volunteers leads to an increase in serum interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha and a significant decrease in cytochrome P450 (CUP)-mediated d rug metabolism. The in vivo effects of the noninflammatory cytokine interle ukin-10 (IL-10) on GYP-mediated drug metabolism vp was examined. Methods: IL-10 (8 mu g/kg) and placebo were administered for 6 days to 12 h ealthy volunteers in a double-blind crossover study. Tolbutamide (CYP2C9), caffeine (CYP1A2), dextromethorphan (CYP2D6 and CYP3A), and midazolam (CYP3 A) were administered on days 4 and 5 to determine individual CUP activities . Results: Few clinically apparent side effects were observed after administr ation of IL-10; however, blood chemistries reflected-an acute-phase respons e, A significant drop in serum albumin (mean percentage change +/- SD betwe en groups; 4.7% +/- 6.0%, P less than or equal to.02), a significant increa se in serum ferritin (736% +/- 717%, P less than or equal to.001), and a si gnificant reduction in platelet count (49% +/- 12%, P less than or equal to .0001) was observed after administration of IL-10, IL-IO significantly (P l ess than or equal to.02) decreased CYP3A activity 12% +/- 17%, as reflected by midazolam clearance. CYP2C9 activity was significantly (P less than or equal to.005) increased by 38% +/- 35%, as reflected by the tolbutamide uri nary metabolic ratio and oral clearance. However, administration of IL-IO r esulted in a 40% increase in the fraction unbound of tolbutamide, Therefore no difference in the unbound clearance of tolbutamide was observed between placebo (23.3 +/- 9.7 L/h) or IL-10 (23.5 +/- 11.4 L/h) administration, No significant changes in either CYP1A2 or CYP2D6 activities were observed: b etween placebo and treatment arms of the study, Conclusion: IL-10 administration resulted in an acute-phase response. Admin istration of IL-10 did not alter CYP1A2, CYP2C9, and CYP2D6 activities. CYP 3A-mediated biotransformation was reduced by administration of IL-10.