Effect of interleukin 6 on the hepatic metabolism of itraconazole and its metabolite hydroxyitraconazole using primary human hepatocytes.
A potential cytokine-drug interaction between interleukin 6 (IL-6) and itraconazole (ITZ) was studied using human hepatocytes in primary culture. Cultures from 5 adult males (mean age 42 +/- 15 years) who had not received any medicines known to interact with CYP3A4 were studied. Cultures were exposed to ITZ 500 ng/ml, and the effects of 120 microg/ml cimetidine, 50 ng/ml human IL-6, or IL-6 plus IL-6 receptor antagonist were analyzed for 2, 4, 8, and 12 h. Intracellular ITZ and hydroxyitraconazole concentrations were measured using HPLC and normalized to total cellular protein. Mean intracellular concentrations between groups were compared using one-way Anova (f test; p < 0.10) and corresponding Bonferroni versus control test for multiple comparisons (p < 0.02). Mean intracellular ITZ concentrations between the groups were similar at all time points. Human hepatocytes in primary culture can metabolize ITZ. However, IL-6 did not inhibit hydroxyitraconazole formation, but it may inhibit its subsequent metabolism.
Gubbins
P O
PO
Department of Pharmacy Practice, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 W Markham, Slot 522, Little Rock, AR 7225-7122, USA. Gubbinspaulo@uams.edu
Melchert
R B
RB
McConnell
S A
SA
Franks
A M
AM
Penzak
S R
SR
Gurley
B J
BJ
D000328:Adult; D002478:Cells, Cultured; D002927:Cimetidine / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D017964:Itraconazole / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C084794:hydroxyitraconazole; D017964:Itraconazole; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System