Differential effect of IFNalpha-2b on the cytochrome P450 enzyme system: a potential basis of IFN toxicity and its modulation by other drugs.
OBJECTIVE
High-dose IFNalpha-2b therapy (HDI) is the standard of adjuvant therapy for patients with high-risk melanoma, but toxicities of this regimen have limited its application. IFNs affect cytochrome P450 (CYP) enzymes, which metabolize many endogenous (e.g., steroids, fatty acids) and exogenous (e.g., drugs) substrates. No systematic studies have been performed to evaluate the effect of HDI on CYP enzymes. A significant inhibitory effect of HDI on CYP enzymes would increase the potential for adverse drug reactions and altered homeostasis through effects on hormone metabolism.


METHODS
To evaluate the potential effect of HDI on CYP enzymes, 17 patients with high-risk melanoma were treated with HDI, and CYP enzyme activity was measured by administration of selectively metabolized probe drugs over time (days -6, +1, +26, and +52 of HDI). Probe drugs and/or metabolites were quantified and used to derive indexes of enzyme activity.


RESULTS
The results indicate that HDI differentially impairs CYP-mediated metabolism, having no effect on some enzymes (CYP2E1) and substantial effects on others (CYP1A2; median 60% decrease). A significant association was found between the magnitude of CYP inhibition and the occurrence of side effects including fever and neurological toxicity, which may form a novel basis of the underlying pathophysiology of some IFNalpha-2b-induced toxicity.


CONCLUSIONS
These data suggest that strategies to minimize the impairment of CYP enzymes could alter the toxicity profile of HDI and augment its therapeutic utility, and that recognition of these potential interactions is important in the therapeutic application of IFNs.
Islam
Mohammed
M
Melanoma Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
Frye
Reginald F
RF
Richards
Thomas J
TJ
Sbeitan
Ibraham
I
Donnelly
Sandra S
SS
Glue
Paul
P
Agarwala
Sanjiv S
SS
Kirkwood
John M
JM
D017024:Chemotherapy, Adjuvant; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000493:pharmacokinetics*; D016015:Logistic Models; D008545:Melanoma / Q000188:drug therapy / Q000601:surgery; D020033:Protein Isoforms; D011994:Recombinant Proteins; D013997:Time Factors
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D020033:Protein Isoforms; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6