Effects of interferon-alpha monotherapy on hepatic drug metabolism in cancer patients.
1. The influence of interferon-alpha (IFN alpha) on the clearances of theophylline (TH), antipyrine (AP) and hexobarbitone (HB) was studied in seven cancer patients given IFN alpha as their only treatment. In addition, IFN alpha effects on drug clearance were correlated with changes in serum inflammatory cytokines and acute phase proteins. 2. A 'baseline' study was performed by administering an oral drug 'cocktail' of TH (150 mg), AP (250 mg) and HB (250 mg) with saline injected simultaneously and again 24 h later. One week later, an 'acute' study was performed at the initiation of IFN alpha therapy, 3 x 10(6) units injected with the drug cocktail and again 24 h later. After 2 weeks of IFN alpha treatment three times per week, a 'chronic' study was performed with IFN alpha injected the day prior to, simultaneously with, as well as 24 h after the drug cocktail. 3. Plasma samples were collected over 48 h and the clearances of TH, AP and HB were estimated. Serum samples were collected at various times for the measurement of tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), C-reactive protein (C-RP) and alpha 1-acid glycoprotein (AGP). 4. IFN alpha caused a 33% decrease in the oral clearance of TH during the chronic study compared with baseline (P < or = 0.05). Although IFN alpha inhibited TH clearance by 16% during the acute study and AP clearance by 20-21% during both acute and chronic studies, these changes did not reach statistical significance. IFN alpha caused minimal changes in HB clearance. There were no chronic effects of IFN alpha on serum cytokines or acute phase proteins. 5. The findings confirm that the most commonly used dose of IFN alpha inhibits the hepatic clearance in humans of some but not all drugs and that this inhibition persists during IFN alpha therapy. Because inhibition was not associated with increases in serum cytokines or acute phase proteins, the mechanism by which IFN alpha inhibits cytochrome P450 activities in vivo does not appear to involve inflammatory mediators such as TNF. IL-1 or IL-6.
Israel
B C
BC
Division of Pharmacology and Experimental Therapeutics, College of Pharmacy, Lexington, Kentucky, USA.
Blouin
R A
RA
McIntyre
W
W
Shedlofsky
S I
SI
D000368:Aged; D000983:Antipyrine / Q000493:pharmacokinetics; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D006591:Hexobarbital / Q000493:pharmacokinetics; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D013806:Theophylline / Q000493:pharmacokinetics
D065607:Cytochrome P-450 Enzyme Inhibitors; D016898:Interferon-alpha; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D013806:Theophylline; D000983:Antipyrine