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-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.


CONCLUSIONS
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.
Gorski
J C
JC
Department of Medicine, Indiana University School of Medicine, Indianapolis 46202, USA.
Hall
S D
SD
Becker
P
P
Affrime
M B
MB
Cutler
D L
DL
Haehner-Daniels
B
B
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004311:Double-Blind Method; D005293:Ferritins / Q000097:blood; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D016753:Interleukin-10 / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects; D010976:Platelet Count / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D012709:Serum Albumin / Q000187:drug effects; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000187:drug effects
D006454:Hemoglobins; D011994:Recombinant Proteins; D012709:Serum Albumin; D016753:Interleukin-10; D005293:Ferritins; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D039181:Steroid 16-alpha-Hydroxylase; D010089:Oxidoreductases, N-Demethylating