Docetaxel (Taxotere), a semi-synthetic analog of paclitaxel (Taxol), is a promoter of microtubule polymerization leading to cell cycle arrest at G2/M, apoptosis and cytotoxicity. Docetaxel has significant activity in breast, non-small-cell lung, ovarian and head and neck cancers. Docetaxel has undergone phase I study in a number of schedules, including different infusion durations and various treatment cycles. Doses studied in adults have ranged from 5 to 145 mg/m2 and those in children from 55 to 235 mg/m2. The most frequently used regimen in adults is 100 mg/m2 every 3 weeks. A 1-hour infusion every 3 weeks has been favoured in phase II and III studies, and the disposition of docetaxel after such treatment is best described by a 3 compartment model with alpha, beta and gamma half-lives of 4.5 minutes, 38.3 minutes and 12.2 hours, respectively. The disposition of docetaxel appears to be linear, the area under the plasma concentration-time curve (AUC) increasing proportionately with dose. Docetaxel is widely distributed in tissues with a mean volume of distribution of 74 L/m2 after 100 mg/m2, every 3 weeks. The mean total body clearance after this schedule is approximately 22 L/h/m2, principally because of hepatic metabolism by the cytochrome P450 (CYP)3A4 system and biliary excretion into the faeces. Renal excretion is minimal (< 5%). Docetaxel is > 90% bound in plasma. Population pharmacokinetic studies of docetaxel have demonstrated that clearance is significantly decreased with age, decreased body surface area, increased concentrations of alpha 1-acid glycoproteinand albumin. Importantly, patients with elevated plasma levels of bilirubin and/or transaminases have a 12 to 27% decrease in docetaxel clearance and should receive reduced doses. Although docetaxel is metabolised by CYP3A4, phase I combination studies have not shown major evidence of significant interaction between docetaxel and other drugs metabolised by the same pathway. Nevertheless, care should be taken with the use of known CYP3A4 inhibitors such as erythromycin, ketoconazole and cyclosporin. Conversely, increased doses may be required for patients receiving therapy known to induce this cytochrome (e.g. anticonvulsants). Perliminary data suggest the erythromycin breath test, an indicator of CYP3A4 function, is a predictor of toxicity after treatment with docetaxel. Such methodologies may eventually enable clinicians to individualise doses of docetaxel for patients with cancer.
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.
The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.
Purpose: The purpose is to identify the demographic, physiologic, and inheritable factors that influence CYP3A activity in cancer patientsExperimental Design: A total of 134 patients (62 females; age range, 26 to 83 years) underwent the erythromycin breath test as a phenotyping probe of CYP3A. Genomic DNA was screened for six variants of suspected functional relevance in CYP3A4 (CYP3A4*1B, CYP3A4*6, CYP3A4*17, and CYP3A4*18) and CYP3A5 (CYP3A5*3C and CYP3A5*6).Results: CYP3A activity (AUC 0 -40min ) varied up to 14-fold in this population. No variants in the CYP3A4 and CYP3A5 genes were a significant predictor of CYP3A activity (P > 0.2954). CYP3A activity was reduced by ϳ50% in patients with concurrent elevations in liver transaminases and alkaline phosphatase or elevated total bilirubin (P < 0.001). In a multivariate analysis, CYP3A activity was not significantly influenced by age, sex, and body size measures (P > 0.05), but liver function combined with the concentration of the acute-phase reactant, ␣-1 acid glycoprotein, explained ϳ18% of overall variation in CYP3A activity (P < 0.001).Conclusions: These data suggest that baseline demographic, physiologic, and chosen genetic polymorphisms have a minor impact on phenotypic CYP3A activity in patients with cancer. Consideration of additional factors, including the inflammation marker C-reactive protein, as well as concomitant use of other drugs, food constituents, and complementary and alternative medicine with inhibitory and inducible effects on CYP3A, is needed to reduce variation in CYP3A and treatment outcome to anticancer therapy.
Purpose: Many chemotherapeutic drugs have an inherent lack of safety due to interindividual variability of hepatic cytochrome P450 (CYP) 3A4 drug metabolism. This reduction in CYP3A4 in cancer patients is possibly mediated by cytokines associated with tumor-derived inflammation. We sought to examine this link by using an explant sarcoma in a novel transgenic mouse model of human CYP3A4 regulation. Experimental Design: Engelbreth-Holm-Swarm sarcoma cells were injected into the hindlimb of transgenic CYP3A4/lacZ mice. Hepatic expression of the human CYP3A4 transgene was analyzed by direct measurement of the reporter gene product, h-galactosidase enzyme activity. Hepatic expression of murine Cyp3a was analyzed at the mRNA, protein, and function levels. The acute phase response was assessed by examining cytokines and tumor necrosis factor] in serum, liver, or tumor as well as hepatic expression of serum amyloid protein P. Results: Engelbreth-Holm-Swarm sarcoma elicited an acute phase response that coincided with down-regulation of the human CYP3A4 transgene in the liver as well as the mouse orthologue Cyp3a11. The reduction of murine hepatic Cyp3a gene expression in tumor-bearing mice resulted in decreased Cyp3a protein expression and consequently a significant reduction in Cyp3a-mediated metabolism of midazolam. Circulating IL-6 was elevated and IL-6 protein was only detected in tumor tissue but not in hepatic tissue. Conclusions:The current study provides a mechanistic link between cancer-associated inflammation and impaired drug metabolism in vivo. Targeted therapy to reduce inflammation may provide improved clinical benefit for chemotherapy drugs metabolized by hepatic CYP3A4 by improving their pharmacokinetic profile.The pharmacokinetics of anticancer drugs vary substantially between patients and are an important causative factor in their inherent lack of safety. Much of the interpatient variability in the clearance of anticancer drugs can be attributed to differences in the levels of drug metabolizing enzymes, especially cytochrome P450 (CYP) 3A4. CYP3A4 is responsible for the metabolism of many important classes of anticancer drugs, including the taxanes, Vinca alkaloids, and camptothecins (1). We have observed previously that patients with advanced cancer have significantly reduced CYP3A4 activity (2) associated with increased plasma concentrations of inflammatory mediators, in particular interleukin-6 (IL-6) and C-reactive protein (3). Importantly, impaired CYP3A4-mediated clearance was correlated with increased toxicity to docetaxel and vinorelbine (2). IL-6 is one of several proinflammatory cytokines with proven involvement in tumor growth, invasion, and metastasis in several malignancies (4) and is associated with initiation of many clinical features of malignancy (i.e., fevers, weight loss, and fatigue; ref. 5). A systemic inflammatory response, as indicated by elevated C-reactive protein, is a prognostic indicator of poor outcome in numerous malignancies, including adenocarcinoma of the pancr...
Irinotecan (CPT-11) is an anticancer drug that occasionally produces acute cholinergic side effects. Preliminary findings suggest that these are mediated through the inhibition of acetylcholinesterase (AChE). In this study, the inhibition of various AChEs by CPT-11 was studied. The lactone form of CPT-11 resulted in apparent noncompetitive inhibition of electric eel and both human recombinant and erythrocyte AChE with K(i) values of 0.065, 0.19, and 0.29 microM, respectively. The carboxylate form of CPT-11 was approximately 10 times less potent. Apparent noncompetitive inhibition of AChE may arise through several mechanisms, and those relevant to CPT-11 were identified from key experimental findings. First, the inhibition by CPT-11 was found to be instantly reversible in dilution studies. Second, incubation of the enzyme with CPT-11 before the introduction of neostigmine protected the enzyme from inactivation. Third, regeneration of the active enzyme after preincubation with neostigmine was totally suppressed by the addition of 2 microM CPT-11, indicating that CPT-11 is a potent inhibitor of decarbamoylation and, by inference, deacylation. Additional experiments with tacrine revealed functional differences between these two inhibitors. Also, preliminary molecular modeling of the interaction between AChE and CPT-11 indicated that the latter does not bind at the same site as tacrine. Displacement studies with the peripheral site-specific ligand, propidium, confirmed that CPT-11 binds at this site. The rapid reversibility of the inhibition of AChE by CPT-11 and the lower activity of the carboxylate form are likely reasons for the transient nature of the cholinergic toxicity observed clinically.
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