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Differential Effect of IFN-2b on the Cytochrome P450 Enzyme System: A Potential Basis of IFN Toxicity and Its Modulation by Other Drugs¹

Melanoma Center, University of Pittsburgh Cancer Institute [M. I., T. J. R., I. S., S. S. D., S. S. A., J. M. K.], Department of Medicine, School of Medicine [J. M. K.], and Department of Pharmaceutical Sciences, School of Pharmacy and Center for Clinical Pharmacology [R. F. F.], University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and Schering Plough Research Institute, Kennilworth, New Jersey 07033 [P. G.]

Purpose: High-dose IFN-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 IFN-2b-induced toxicity.

Conclusion: 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.

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