Hepatic cytochrome P450 3A drug metabolism is reduced in cancer patients who have an acute-phase response

Abstract

Inflammatory disease states (infection, arthritis) are associated with reduced drug oxidation by the cytochrome P450 3A system. Many chemotherapy agents are metabolised through this pathway, and disease may therefore influence inter-individual differences in drug pharmacokinetics. The purpose of this study was to assess cytochrome P450 3A function in patients with advanced cancer, and its relation to the acute-phase response. We evaluated hepatic cytochrome P450 3A function in 40 patients with advanced cancer using the erythromycin breath test. Both the traditional C 20min measure and the recently proposed 1/T MAX values were estimated. The marker of acute-phase response, C-reactive protein and the pro-inflammatory cytokines IL-6, IL-1b, TNFa and IL-8 were measured in serum or plasma at baseline. Cancer patients with an acute phase response (C-reactive protein 410 mg l 71 , n=26) had reduced metabolism as measured with the erythromycin breath test 1/ T MAX (Kruskal -Wallis Anova, P=0.0062) as compared to controls (C-reactive protein 410 mg l 71 , n=14) . Indeed, metabolism was significantly associated with C-reactive protein over the whole concentration range of this acute-phase marker (r=70.64, Spearman Rank Correlation, P50.00001). C-reactive protein serum levels were significantly correlated with those of IL-6 (Spearman coefficient=0.58, P50.0003). The reduction in cytochrome P450 3A function with acute-phase reaction was independent of the tumour type and C-reactive protein elevation was associated with poor performance status. This indicates that the sub-group of cancer patients with significant acute-phase response have compromised drug metabolism, which may have implications for the safety of chemotherapy in this population.

Comparison of an inflammation-based prognostic score (GPS) with performance status (ECOG) in patients receiving platinum-based chemotherapy for inoperable non-small-cell lung cancer

“…More recently, it has been reported that cytochrome P450 3A activity, the principal drug metabolising enzyme in a variety of chemotherapeutic agents, is compromised in advanced lung cancer patients with an elevated C-reactive protein concentration (Rivory et al, 2002;Slaviero et al, 2003). One might therefore postulate that the presence of a systemic inflammatory response would be associated with increased toxicity in patients receiving platinumbased chemotherapy.…”

The systemic inflammatory response, performance status and survival in patients undergoing alpha-interferon treatment for advanced renal cancer

“…However, it is likely to be linked to increased toxicity in these patients. Therefore, it is of interest that the activity of the enzyme cytochrome P450 3A, involved in biotransformation of more than half of all drugs currently available, is compromised in patients with an elevated C-reactive protein concentration (Rivory et al, 2002;Slaviero et al, 2003). It may be that moderation of the systemic inflammatory response will reduce such toxicity.…”

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

“…These factors can have an impact on drug disposition, resulting in either ineffective drug doses or excessive toxicity (Thummel and Wilkinson, 1998;Schuetz, 2004). This concept is supported by a study demonstrating that reductions in CYP3A4 activity in patients with advanced cancer were correlated to an increased plasma concentration of the inflammatory mediators interleukin (IL-)6 and C-reactive protein (CRP) (Rivory et al, 2002;Slaviero et al, 2003). This was associated with reduced clearance and increased toxicity from docetaxel, a well-characterised substrate for CYP3A4.…”