Interleukins-12 and -23 Do Not Alter Expression or Activity of Multiple Cytochrome P450 Enzymes in Cryopreserved Human Hepatocytes

Abstract

Psoriasis is a T-cell-mediated autoimmune disease involving the skin. Two cytokines, interleukin-12 (IL-12) and IL-23 have been shown to play a pivotal role in the pathogenesis of the disease. Ustekinumab (Stelara) is a therapeutic monoclonal antibody (mAb) targeted against the p40 shared subunit of . Recently the ability of therapeutic proteins (TP) including mAbs that target either cytokines directly (e.g., Pegasys; peginterferon a-2a) or their respective cell surface receptors [e.g., tocilizumab (Actemra); anti IL-6R] to desuppress cytochrome P450 (P450) enzymes in vitro and in the clinic, has been demonstrated. In the present study the ability of IL-12 and IL-23 to suppress multiple P450 enzymes was investigated in vitro using six separate lots of cultured human hepatocytes. Following exposure of 10 ng/ml IL-12 and IL-23 for 48 hours, either alone or in combination, no change in CYP2B6, 2C9, 2C19, or 3A4 gene expression or functional activity was observed. None of the untreated hepatocyte donors showed appreciable expression of the IL-12 or IL-23 receptors. Similar results were seen with whole human liver samples. Exposure of hepatocytes to IL-12 and/or IL-23, known P450 suppressors (IL-6 and tumor necrosis factor-a) or known P450 inducers (b-naphthoflavone, phenobarbital, and rifampicin) did not appreciably alter the expression of the IL-12 and IL-23 receptors either. Finally, in contrast to the positive control IL-6, expression of the acute phase C-reactive protein was unaltered following IL-12 and/or IL-23 treatment. Together, these data suggest a negligible propensity for IL-12 or IL-23 to directly alter P450 enzymes in human hepatocytes. IntroductionThe ability of therapeutic proteins (TP) that target cytokines to potentially mediate drug interactions through alterations in drug metabolizing enzymes is a growing concern in drug development (Huang et al., 2010). Patients with inflammatory disease often have increased circulating or local cytokine levels including interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), and interferon-gamma, which have all been shown to alter cytochrome P450 (P450) metabolic enzyme levels in the liver (Morgan, 2009). The TP treatment that neutralizes one or more of these cytokines could result in patients experiencing rebound metabolic enzyme levels, leading to decreased comedication exposure and potentially therapeutic failure. As an example, recent clinical studies by Schmitt et al., (2011) showed significantly decreased simvastatin (Zocor) exposure in rheumatoid arthritis patients receiving tocilizumab, an anti-human IL-6 receptor mAb. The decreased exposure was linked to changes in CYP3A4 expression reported by the same group following anti-IL-6R treatment in the presence and absence of tocilizumab in cultured human hepatocytes (Zhang et al., 2009).Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the population (Christophers, 2001;Nestle et al., 2009). Pathogenesis of psoriasis involves a complex interplay of various cytokines, incl...

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Inflammation-Induced Phenoconversion of Polymorphic Drug Metabolizing Enzymes: Hypothesis with Implications for Personalized Medicine

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Critical Review of Preclinical Approaches to Investigate Cytochrome P450–Mediated Therapeutic Protein Drug-Drug Interactions and Recommendations for Best Practices: A White Paper

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