BACKGROUND: Injection of lipopolysaccharide into human volunteers leads to an increase in serum interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha and a significant decrease in cytochrome P450 (CYP)-mediated drug metabolism. The in vivo effects of the noninflammatory cytokine interleukin-10 (IL-10) on CYP-mediated drug metabolism was examined. METHODS:IL-10 (8 microg/kg) and placebo were administered for 6 days to 12 healthy volunteers in a double-blind crossover study. Tolbutamide (CYP2C9), caffeine (CYP1A2), dextromethorphan (CYP2D6 and CYP3A), and midazolam (CYP3A) were administered on days 4 and 5 to determine individual CYP activities. RESULTS: Few clinically apparent side effects were observed after administration of IL-10; however, blood chemistries reflected an acute-phase response. A significant drop in serum albumin (mean percentage change +/- SD between groups; 4.7% +/- 6.0%, P < or = .02), a significant increase in serum ferritin (736% +/- 717%, P < or = .001), and a significant reduction in platelet count (49% +/- 12%, P < or = .0001) was observed after administration of IL-10. IL-10 significantly (P < or = .02) decreased CYP3A activity 12% +/- 17%, as reflected by midazolam clearance. CYP2C9 activity was significantly (P < or = .005) increased by 38% +/- 35%, as reflected by the tolbutamide urinary metabolic ratio and oral clearance. However, administration of IL-10 resulted 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 between placebo and treatment arms of the study. CONCLUSION:IL-10 administration resulted in an acute-phase response. Administration of IL-10 did not alter CYP1A2, CYP2C9, and CYP2D6 activities. CYP3A-mediated biotransformation was reduced by administration of IL-10.
RCT Entities:
BACKGROUND: Injection of lipopolysaccharide into human volunteers leads to an increase in serum interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha and a significant decrease in cytochrome P450 (CYP)-mediated drug metabolism. The in vivo effects of the noninflammatory cytokine interleukin-10 (IL-10) on CYP-mediated drug metabolism was examined. METHODS:IL-10 (8 microg/kg) and placebo were administered for 6 days to 12 healthy volunteers in a double-blind crossover study. Tolbutamide (CYP2C9), caffeine (CYP1A2), dextromethorphan (CYP2D6 and CYP3A), and midazolam (CYP3A) were administered on days 4 and 5 to determine individual CYP activities. RESULTS: Few clinically apparent side effects were observed after administration of IL-10; however, blood chemistries reflected an acute-phase response. A significant drop in serum albumin (mean percentage change +/- SD between groups; 4.7% +/- 6.0%, P < or = .02), a significant increase in serum ferritin (736% +/- 717%, P < or = .001), and a significant reduction in platelet count (49% +/- 12%, P < or = .0001) was observed after administration of IL-10. IL-10 significantly (P < or = .02) decreased CYP3A activity 12% +/- 17%, as reflected by midazolam clearance. CYP2C9 activity was significantly (P < or = .005) increased by 38% +/- 35%, as reflected by the tolbutamide urinary metabolic ratio and oral clearance. However, administration of IL-10 resulted 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 between placebo and treatment arms of the study. CONCLUSION:IL-10 administration resulted in an acute-phase response. Administration of IL-10 did not alter CYP1A2, CYP2C9, and CYP2D6 activities. CYP3A-mediated biotransformation was reduced by administration of IL-10.
Authors: Gail D Anderson; Todd C Peterson; Cole Vonder Haar; Fred M Farin; Theo K Bammler; James W MacDonald; Eric D Kantor; Michael R Hoane Journal: AAPS J Date: 2015-06-12 Impact factor: 4.009