Acute-phase response, interleukin-6, and alteration of cyclosporine pharmacokinetics

Chen, Yan Lian; Vraux, Valérie Le; Leneveu, A; Dreyfus, F.; Stheneur, A.; Florentin, I.; Sousa, Martine De; Giroud, J. P.; Flouvat, B; Chauvelot‐Moachon, Laurence

doi:10.1038/clpt.1994.82

Cited by 111 publications

(95 citation statements)

References 3 publications

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“…Also, it has been noted that the clearance of hepatically metabolised drugs is sometimes reduced in xenograft-bearing animals, even when these are not bound to AAG (Zamboni et al, 1998). Finally, there is evidence in support of a direct effect of pro-inflammatory cytokines on CYP3A expression, activity and drug clearance (Moreno et al, 1991;Craig et al, 1993;Chen et al, 1994;Muntane-Relat et al, 1995;Morgan, 1997;Pascussi et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Pro-inflammatory cytokines and acute-phase reactants are elevated in many patients with advanced cancer (Heys et al, 1998;Martin et al, 1999) and there is, therefore, the possibility that part of the inter-individual variability in drug clearance and toxicity could relate to the effects of these cytokines on CYP3A expression (Moreno et al, 1991;Craig et al, 1993;Chen et al, 1994;Muntane-Relat et al, 1995;Morgan, 1997;Pascussi et al, 2000). Further falls in CYP3A function may occur with age (Hunt et al, 1990) and reduced hepatic drug clearance may contribute to a greater risk of adverse events in elderly cancer patients (Yancik et al, 1998).…”

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confidence: 99%

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

Rivory

Slaviero

Clarke³

2002

Br J Cancer

195

153

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Rivory

Slaviero

Clarke³

2002

Br J Cancer

195

153

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“…The relationship between inflammation and repression of P450 activity, in particular CYP3A4, has been extensively studied both in vitro and in vivo (Chen et al, 1994;Carcillo et al, 2003;Haack et al, 2003). These studies consistently illustrate reduced hepatic expression of CYPs in the presence of acute inflammation, mediated primarily by the proinflammatory cytokines IL-6, IL-1b and tumour necrosis factor-a (TNF-a), resulting in reduced drug metabolism and clearance (Morgan, 1997(Morgan, , 2001Fang et al, 2004).…”

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confidence: 99%

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

et al. 2007

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There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism.

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“…It is possible that the inhibitory effect of delavirdine on ritonavir clearance is more pronounced at the higher ritonavir concentrations, since ritonavir exhibits nonlinear pharmacokinetics (10). Subject differences (healthy volunteers versus HIV-1-infected patients) may also have contributed to the difference between study results regarding the effect of delavirdine on ritonavir clearance; altered patterns of drug metabolism have been observed in HIV-1-infected patients relative to those in normal volunteers (3,4,12,15,16). The concentration-time profiles for delavirdine in the present study generally differed from those in previous steady-state studies with either fasting or fed HIV-1-infected patients, and this difference is consistent with a more delayed and/or prolonged drug absorption (1, 2, 7).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Ritonavir and Delavirdine in Human Immunodeficiency Virus-Infected Patients

Shelton

Hewitt

Adams

et al. 2003

Antimicrob Agents Chemother

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To evaluate the pharmacokinetic effect of adding delavirdine mesylate to the antiretroviral regimens of human immunodeficiency virus (HIV)-infected patients stabilized on a full dosage of ritonavir (600 mg every 12 h), 12 HIV-1-infected subjects had delavirdine mesylate (400 mg every 8 h) added to their current antiretroviral regimens for 21 days. Ritonavir pharmacokinetics were evaluated before (day 7) and after (day 28) the addition of delavirdine, and delavirdine pharmacokinetics were evaluated on day 28. The mean values (؎ standard deviations) for the maximum concentration in serum (C max ) of ritonavir, the area under the concentration-time curve from 0 to 12 h (AUC 0-12 ), and the minimum concentration in serum (C min ) of ritonavir before the addition of delavirdine were 14.8 ؎ 6.7 M, 94 ؎ 36 M ⅐ h, and 3.6 ؎ 2.1 M, respectively. These same parameters were increased to 24.6 ؎ 13.9 M, 154 ؎ 83 M ⅐ h, and 6.52 ؎ 4.85 M, respectively, after the addition of delavirdine (P is <0.05 for all comparisons). Delavirdine pharmacokinetic parameters in the presence of ritonavir included a C max of 23 ؎ 16 M, an AUC 0-8 of 114 ؎ 75 M ⅐ h, and a C min of 9.1 ؎ 7.5 M. Therefore, delavirdine increases systemic exposure to ritonavir by 50 to 80% when the drugs are coadministered.

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Acute-phase response, interleukin-6, and alteration of cyclosporine pharmacokinetics

Cited by 111 publications

References 3 publications

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

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

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

Pharmacokinetics of Ritonavir and Delavirdine in Human Immunodeficiency Virus-Infected Patients

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