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

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-1beta, TNFalpha and IL-8 were measured in serum or plasma at baseline. Cancer patients with an acute phase response (C-reactive protein >10 mg x l(-1), 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 < or =10 mg x l(-1), n=14) Indeed, metabolism was significantly associated with C-reactive protein over the whole concentration range of this acute-phase marker (r=-0.64, Spearman Rank Correlation, P<0.00001). C-reactive protein serum levels were significantly correlated with those of IL-6 (Spearman coefficient=0.58, P<0.0003). 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.

The erythromycin breath test for the prediction of drug clearance.

The erythromycin breath test (EBT) is a putative probe of cytochrome P450 (CYP) 3A4 activity in vivo. Therefore, the EBT might prove useful for the individualisation of doses of drugs that have a low therapeutic window (for example the immunosuppressants or cytotoxics) and are metabolised by CYP3A4. However, there is a lack of consensus as to how the EBT should be used to predict total body clearance (CL), and the results so far have been largely disappointing. We argue that the required assumption that individuals produce 5 mmol of CO2/min per m2 at rest is one of the problems with the existing EBT, as the literature suggests significant variability and possible gender differences in this parameter. An examination of the EBT with a simple compartment model suggests that alternative parameters could be more useful in the prediction of CL. In particular, there is theoretical support for the use of the time-point at which breath radioactivity is maximal (tmax) as a correlate for CL. This is in agreement with our recent study of the pharmacokinetics of erythromycin in patients with cancer.

Optimizing the erythromycin breath test for use in cancer patients.

The erythromycin breath test (EBT) is a putative in vivo probe for drug metabolism by cytochrome P450 3A4 (CYP3A4). Because many anticancer drugs are metabolized by this system, we sought to further develop the EBT as a tool for predicting the clearance, in cancer patients, of drugs metabolized by CYP3A4. Sixteen adult patients with incurable cancer were studied. The EBT was performed on day 1 and breath sampled after the i.v. injection of 4 microCi of 14C-erythromycin. The breath 14CO2 flux (CERt) was estimated at 11 time points over 2 h. On day 2, the EBT was repeated midway through a 10-min infusion of 100 mg of erythromycin lactobionate, and the plasma pharmacokinetics of erythromycin were determined. The infusion of 100 mg of erythromycin did not modify the EBT results significantly. The values of the conventional EBT parameter CER20 min obtained on day 1 were comparable for most subjects (0.03-0.06% dose/min), with the exception of an individual receiving the known CYP3A4 inducers dexamethasone and phenytoin who returned a value of 0.14% dose/min. There was no significant correlation between any of the conventional EBT parameters and erythromycin clearance. However, two parameters reflecting early emergence of breath radioactivity (1/TMAX and CER3 min/CERMAX) correlated significantly with erythromycin clearance (P = 0.005 and 0.006, respectively). Novel parameters derived from the EBT are significantly correlated with the clearance of erythromycin even in the presence of confounding factors, such as metastatic liver disease, altered protein binding, and comedication. These parameters may enable dose optimization of cytotoxics metabolized by CYP3A4.