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1.
Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec,STI571) in healthy subjects 总被引:1,自引:0,他引:1
Bolton AE Peng B Hubert M Krebs-Brown A Capdeville R Keller U Seiberling M 《Cancer chemotherapy and pharmacology》2004,53(2):102-106
Objective This study was carried out to investigate the influence of CYP3A induction with rifampicin on imatinib (Gleevec) exposure.Methods The study employed a single center, single-sequence design. A group of 14 healthy male and female subjects received imatinib as a single 400 mg oral dose on two occasions: on study day 1 and on study day 15. Rifampicin treatment (600 mg once daily) for CYP4503A induction was initiated on study day 8 and maintained until day 18. Imatinib pharmacokinetics were determined up to 96 h after dosing on day 1 (no induction) and on days 15–18 (during concomitant rifampicin). Plasma concentrations of imatinib and its main metabolite CGP74588 were determined using a LC/MS/MS method. The ratio of 6-hydroxycortisol to cortisol excreted in the urine was measured to monitor the induction of CYP3A.Results During concomitant rifampicin administration, the mean imatinib Cmax, AUC0–24 and AUC0– decreased by 54% (90% CI: 48–60%), 68% (64–70%) and 74% (71–76%), respectively. The increase in clearance (Cl/f) was 385% (348–426%) during rifampicin treatment. The mean Cmax and AUC0–24 of the metabolite CGP74588 increased by 88.6% (68.3%–111.4%) and 23.9% (13.5%–35.2%) after rifampicin pretreatment. However, the AUC0– decreased by 11.7% (3.3–19.4%). All subjects demonstrated a marked induction of hepatic microsomal CYP3A analyzed by the excretion ratio of 6-hydroxycortisol to cortisol from a mean baseline concentration of 5.6 U to 50.5 U.Conclusion Concomitant use of imatinib and rifampicin or other potent inducers of CYP4503A may result in subtherapeutic plasma concentrations of imatinib. In patients in whom rifampicin or other CYP3A inducers are prescribed, alternative therapeutic agents with less potential for enzyme induction should be selected.This work was submitted as an abstract to the 44th Annual Meeting of The American Society of Hematology (ASH), Philadelphia, USA. Abstract published in Blood, vol 100, no. 11, abstract no. 4364, November 2002.A.E.B., B.P., M.H., A.K.-B. and R.C. are employees of Novartis U.K. and M.S. received grant support from Novartis Pharma AG for the conduct of the study. 相似文献
2.
Smith NF Baker SD Gonzalez FJ Harris JW Figg WD Sparreboom A 《British journal of cancer》2008,98(10):1630-1632
Administration of BAS 100, a novel mechanism-based CYP3A4 inhibitor isolated from grapefruit juice, resulted in a 2.1-fold increase in erlotinib exposure following oral administration to wild-type and humanized CYP3A4 transgenic mice. This study illustrates the potential of BAS 100 to increase the low and variable oral bioavailability of erlotinib in cancer patients. 相似文献
3.
Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel. 总被引:4,自引:0,他引:4
Anja Henningsson Sharon Marsh Walter J Loos Mats O Karlsson Adam Garsa Klaus Mross Stephan Mielke Lucia Viganò Alberta Locatelli Jaap Verweij Alex Sparreboom Howard L McLeod 《Clinical cancer research》2005,11(22):8097-8104
PURPOSE: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). EXPERIMENTAL DESIGN: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m(2)). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with one-way ANOVA. RESULTS: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium. The population typical value of clearance of unbound paclitaxel was 301 L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. CONCLUSIONS: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics. 相似文献
4.
Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics 总被引:1,自引:0,他引:1
Lathia C Lettieri J Cihon F Gallentine M Radtke M Sundaresan P 《Cancer chemotherapy and pharmacology》2006,57(5):685-692
Sorafenib is a novel, small-molecule anticancer compound that inhibits tumor cell proliferation by targeting Raf in the Raf/MEK/ERK
signalling pathway, and inhibits angiogenesis by targeting tyrosine kinases such as vascular-endothelial growth factor receptor
(VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor (PDGFR). In vitro microsomal data indicate that sorafenib
is metabolized by two pathways: phase I oxidation mediated by cytochrome P450 (CYP) 3A4; and phase II conjugation mediated
by UGT1A9. Approximately 50% of an orally administered dose is recovered as unchanged drug in the feces, due to either biliary
excretion or lack of absorption. The aim of this study was to evaluate the effect of CYP3A inhibition by ketoconazole on sorafenib
pharmacokinetics. This was an open-label, non-randomized, 2-period, one-way crossover study in sixteen healthy male subjects.
A single 50 mg dose of sorafenib was administered alone (period 1) and in combination with ketoconazole 400 mg once daily
(period 2) (ketoconazole was given for 7 days, and a single 50 mg sorafenib dose was administered concomitantly on day 4).
No clinically relevant change in pharmacokinetics of sorafenib and no clinically relevant adverse events or laboratory abnormalities
were observed in this study upon co-administration of the two drugs. Plasma concentrations of the main CYP3A4 generated metabolite,
sorafenib N-oxide, decreased considerably upon ketoconazole co-administration. This effect is in accordance with the in vitro
finding that CYP3A4 is the primary enzyme for sorafenib N-oxide formation. Further, these data indicate that blocking sorafenib
metabolism by the CYP3A4 pathway will not lead to an increase in sorafenib exposure. This is consistent with data from a clinical
mass-balance study that showed 15% of the administered dose was eliminated by glucuronidation, compared to less than 5% eliminated
as oxidative metabolites. Since there was no increase in sorafenib exposure following concomitant administration of the highly
potent CYP3A4 inhibitor ketoconazole with low dose sorafenib, it is postulated that higher therapeutic doses of sorafenib
may be safely co-administered with ketoconazole, as well as with other inhibitors of CYP3A. 相似文献
5.
Sai K Saito Y Fukushima-Uesaka H Kurose K Kaniwa N Kamatani N Shirao K Yamamoto N Hamaguchi T Kunitoh H Ohe Y Tamura T Yamada Y Minami H Ohtsu A Yoshida T Saijo N Sawada J 《Cancer chemotherapy and pharmacology》2008,62(3):529-537
BACKGROUND AND PURPOSE: Cytochrome P450 3A4 (CYP3A4) converts an anticancer prodrug, irinotecan, to inactive metabolites such as APC. However, the contribution of CYP3A4 genetic polymorphisms to irinotecan pharmacokinetics (PK) and pharmacodynamics (PD) is not fully elucidated. In paclitaxel-administered cancer patients, an association of CYP3A4*16B harboring the low activity allele *16 [554C > G (Thr185Ser)] has been shown with altered metabolite/paclitaxel area under the plasma concentration-time curve (AUC) ratios, suggesting a possible impact of *16B on the PK of other drugs. In this study, the effects of CYP3A4 haplotypes including *16B on irinotecan PK/PD were investigated in irinotecan-administered patients. METHODS: The CYP3A4 genotypes for 177 Japanese cancer patients who received irinotecan were defined in terms of 4 major haplotypes, i.e., *1A (wild type), *1G (IVS10 + 12G > A), *16B [554C > G (Thr185Ser) and IVS10 + 12G > A], and *18B [878T > C (Leu293Pro) and IVS10 + 12G > A]. Associations of CYP3A4 genotypes with irinotecan PK and severe toxicities (grade 3 diarrhea and grade 3 or 4 neutropenia) were investigated. RESULTS: Area under the concentration-time curve ratios of APC/irinotecan, an in vivo parameter for CYP3A4 activity, were significantly higher in females than in males. The male patients with *16B showed significantly decreased AUC ratios (APC/irinotecan) with 50% of the median value of the non-*16B male patients (no *16B-bearing female patients in this study), whereas no significant alteration in the AUC ratios was observed in the patients with *18B. A slight trend toward increasing AUC ratios (20%) was detected in both male and female patients bearing *1G. Multivariate analysis confirmed contributions of CYP3A4*16B (coefficient +/- SE = -0.18 +/- 0.077, P = 0.021) and *1G (0.047 +/- 0.021, P = 0.029) to the AUC ratio. However, no significant association was observed between the CYP3A4 genotypes and total clearance of irinotecan or toxicities (severe diarrhea and neutropenia). CONCLUSION: This study suggested that CYP3A4*16B was associated with decreased metabolism of irinotecan to APC. However, the clinical impact of CYP3A4 genotypes on total clearance and irinotecan toxicities was not significant. 相似文献
6.
Nielka P van Erp Hans Gelderblom Mats O Karlsson Jing Li Ming Zhao Jan Ouwerkerk Johan W Nortier Henk-Jan Guchelaar Sharyn D Baker Alex Sparreboom 《Clinical cancer research》2007,13(24):7394-7400
PURPOSE: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. EXPERIMENTAL DESIGN: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day 1) and on the third day (day 4). The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes. RESULTS: In 11 evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days 1 and 4 were 42.6 (33.0-54.9) microg.h/mL and 41.2 (32.1-53.1) microg.h/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 micromol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro. CONCLUSION: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically. 相似文献
7.
Teo YL Saetaew M Chanthawong S Yap YS Chan EC Ho HK Chan A 《Breast cancer research and treatment》2012,133(2):703-711
Concomitant usage of lapatinib, a cytochrome P450 (CYP) 3A4 substrate and dexamethasone, a CYP3A4 inducer, is a pharmacokinetic drug-drug interaction. This combination may increase the formation of reactive lapatinib metabolites, which is potentially hepatotoxic. This study aims to evaluate the clinical effect of dexamethasone on incidence of hepatotoxicity and to ascertain its in vitro role using a parallel cell culture model experimental setup. Clinical effects of dexamethasone on lapatinib-induced hepatotoxicity were evaluated in a nested case-control study based on 120 patient data obtained from our records. For the in vitro experiment, metabolically competent transforming growth factor α mouse hepatocytes (TAMH) were treated with lapatinib and viabilities were compared in the presence or absence of dexamethasone. After adjusting for confounders, patients receiving the combination were 4.57 times (95% CI 1.23-16.88, p = 0.02) more likely to develop hepatotoxicity and 3.48 times (95% CI 1.24-9.80, p = 0.02) more likely to develop a clinically important change in alanine aminotransferase than compared to the other group. Treatment of TAMH cells with lapatinib and dexamethasone caused a further reduction in viability, as compared to treatment with lapatinib alone. At 5 μM lapatinib, the introduction of dexamethasone 20 μM produced a 59% decline in viability. This is the first study to document a clinically important interaction between lapatinib and dexamethasone, which associates with an increased occurrence of hepatotoxicity. The in vitro findings have provided substantiating evidence and insights on the role of dexamethasone in lapatinib-induced hepatotoxicity. 相似文献
8.
J Hirth P B Watkins M Strawderman A Schott R Bruno L H Baker 《Clinical cancer research》2000,6(4):1255-1258
Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4 activity in each patient was measured by the [14C-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2). The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL. The greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals. 相似文献
9.
Chew SC Singh O Chen X Ramasamy RD Kulkarni T Lee EJ Tan EH Lim WT Chowbay B 《Cancer chemotherapy and pharmacology》2011,67(6):1471-1478
Purpose
This exploratory study aimed to explain the interindividual variabilities of docetaxel pharmacokinetics and pharmacodynamics in Asian nasopharyngeal carcinoma patients (n = 54) through the genotyping of CYP3A4, CYP3A5, ABCB1, ABCC2, ABCG2 and SLCO1B3 genes. 相似文献10.
Effect of common CYP3A4 and CYP3A5 variants on the pharmacokinetics of the cytochrome P450 3A phenotyping probe midazolam in cancer patients. 总被引:2,自引:0,他引:2
Erin R Lepper Sharyn D Baker Matt Permenter Nicole Ries Ron H N van Schaik Paul W Schenk Douglas K Price Danielle Ahn Nicola F Smith George Cusatis Roxann G Ingersoll Susan E Bates Ron H J Mathijssen Jaap Verweij William D Figg Alex Sparreboom 《Clinical cancer research》2005,11(20):7398-7404
PURPOSE: To evaluate the effect of naturally occurring variants in genes encoding the cytochrome P450 (CYP) isoforms CYP3A4 and CYP3A5 in patients with cancer receiving midazolam as a phenotyping probe. EXPERIMENTAL DESIGN: Five variants in CYP3A4 and CYP3A5 were evaluated in 58 patients (21 women and 37 men) receiving a short i.v. bolus of midazolam (dose, 0.0145 or 0.025 mg/kg). Midazolam concentrations in plasma were determined using liquid chromatography-mass spectrometry, and pharmacokinetic variables were calculated using noncompartmental analysis. Genomic DNA was characterized for the variants by PCR-RFLP, and all genotypes were confirmed by direct nucleotide sequencing. RESULTS: The mean clearance of midazolam was 24.4 +/- 9.12 L/h, and phenotypic CYP3A activity varied about 4-fold in this population (range, 10.8-44.3 L/h). There were six carriers of the CYP3A4*1B allele (allele frequency, 0.061). No variant alleles for CYP3A4*17, CYP3A4*18A, or CYP3A5*6 were identified. Forty-eight of the 58 patients were homozygous variant for CYP3A5*3C, eight were heterozygous, and two were homozygous wild type (allele frequency, 0.897). No associations were noted between any of the studied genotypes and the phenotypic measures (P > or = 0.16). Likewise, a common variant in exon 26 in the gene encoding P-glycoprotein [i.e., ABCB1 (MDR1) 3435C>T] that was previously reported to be linked to CYP3A4 mRNA levels was unrelated to any of the studied phenotypic measures (P > or = 0.49). CONCLUSIONS: The studied genetic variants in CYP3A4 and CYP3A5 are unlikely to have an important functional significance to phenotypic CYP3A activity in patients with cancer. 相似文献
11.
CYP3A4, CYP3A5, and CYP3A43 genotypes and haplotypes in the etiology and severity of prostate cancer
Zeigler-Johnson C Friebel T Walker AH Wang Y Spangler E Panossian S Patacsil M Aplenc R Wein AJ Malkowicz SB Rebbeck TR 《Cancer research》2004,64(22):8461-8467
The CYP3A genes reside on chromosome 7q21 in a multigene cluster. The enzyme products of CYP3A4 and CYP3A43 are involved in testosterone metabolism. CYP3A4 and CYP3A5 have been associated previously with prostate cancer occurrence and severity. To comprehensively examine the effects of these genes on prostate cancer occurrence and severity, we studied 622 incident prostate cancer cases and 396 controls. Substantial and race-specific linkage disequilibrium was observed between CYP3A4 and CYP3A5 in both races but not between other pairs of loci. We found no association of CYP3A5 genotypes with prostate cancer or disease severity. CYP3A43*3 was associated with family history-positive prostate cancer (age- and race-adjusted odds ratio = 5.86, 95% confidence interval, 1.10-31.16). CYP3A4*1B was associated inversely with the probability of having prostate cancer in Caucasians (age-adjusted odds ratio = 0.54, 95% confidence interval, 0.32-0.94). We also observed significant interactions among these loci associated with prostate cancer occurrence and severity. There were statistically significant differences in haplotype frequencies involving these three genes in high-stage cases (P < 0.05) compared with controls. The observation that CYP3A4 and CYP3A43 were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having prostate cancer and disease severity. 相似文献
12.
13.
Sarah J Plummer David V Conti Pamela L Paris Anthony P Curran Graham Casey John S Witte 《Cancer epidemiology, biomarkers & prevention》2003,12(9):928-932
Previous case-only studies have shown that men with the CYP3A4*1B promoter variant are at an increased risk of developing more aggressive forms of prostate cancer. However, no changes in CYP3A4 activity have been found in CYP3A4*1B carriers, suggesting that its association with disease may simply reflect linkage disequilibrium with another functional variant. CYP3A5 is located within 200 kb of CYP3A4, and a variant in CYP3A5 (*1/*3) correlates with function of the CYP3A5 enzyme. In this study, the potential effect of CYP3A4*1B and CYP3A5*1 on prostate cancer risk and aggressiveness were evaluated in a family-based case-control population. The CYP3A4*1B variant was positively associated with prostate cancer among Caucasians with more aggressive disease [odds ratio (OR), 1.91; 95% confidence interval (CI), 1.02-3.57; P=0.04], and inversely associated with risk among Caucasians with less aggressive disease (OR, 0.08; 95% CI, 0.01-0.49; P=0.006) and men with an age of diagnosis <63 (OR, 0.51; 95% CI, 0.26-1.00; P=0.05). The CYP3A5*1 variant was inversely associated with prostate cancer, especially among Caucasians with less aggressive disease (OR, 0.42; 95% CI, 0.22-0.78; P=0.006). As expected based on these genotype-level results, the CYP3A4*1B/CYP3A5*3 haplotype was positively associated with disease (OR, 2.91; 95% CI, 1.36-6.23; P=0.006), and the CYP3A4*1B/CYP3A5*1 haplotype was inversely associated with risk among Caucasians with less aggressive disease (OR, 0.07; 95% CI, 0.01-0.51; P=0.009). These findings suggest that the CYP3A4 and CYP3A5 variants, or other alleles on the haplotypes they help distinguish, are associated with prostate cancer risk and aggressiveness. 相似文献
14.
Mohammad Safiqul Islam A. G. M. Mostofa Maizbha Uddin Ahmed Muhammad Shahdaat Bin Sayeed Md. Rajib Hassan Abul Hasnat 《Tumour biology》2014,35(2):1671-1678
The rate of direct smoking, second hand smoking, and smokeless tobacco users as well as the amount of environmental pollutant like polycyclic aromatic hydrocarons is increasing in Bangladesh. Therefore, the prevalence of lung cancer is increasing day by day. To the best of our knowledge, no pharmacogentic study of CYP3A4, CYP3A5 genes has been reported on Bangladeshi population relating those with lung cancer. The present study was conducted to determine the association of CYP3A4, CYP3A5 gene polymorphisms and tobacco smoking in the development of lung cancer in Bangladeshi population. A case–control study was carried out on 106 lung cancer patients and 116 controls to investigate three allelic variants—CYP3A4*1B, CYP3A5*3, and CYP3A5*6 using Polymerase Chain Reaction Restriction Fragment Length Polymorphism. Risk of lung cancer was estimated as odds ratio (OR) and 95 % confidence interval (CI) using unconditional logistic regression models. The variant allele frequencies for CYP3A4*1B (*1A/*1B?+?*1B/*1B) were 2.83 % and 0.86 % and that of CYP3A5*3 (*1A/*3?+?*3/*3) were 88.68 % and 85.34 % in cases and controls, respectively. Individual carrying at least one variant allele of CYP3A4*1B (CYP3A4*1A/1B?+?*1B/1B) has a 3.35 times more risk (OR?=?3.35, 95 % Cl?=?0.34-32.71, p?=?0.271) for developing lung cancer whereas individual carrying at least one variant allele of CYP3A5 (CYP3A5*1A/3?+?*3/3) has a 1.26 times more risk (OR?=?1.35, 95 % Cl?=?0.61–2.97) and both are statistically non-significant (p?>?0.05). CYP3A5*6 was absent in the study population. No association of lung cancer with the mentioned polymorphisms was found both in heavy and light smokers. In the cases of all three major types of lung cancer—squamous cell carcinoma, adenocarcinoma, and small cell carcinoma—significantly strong relationships (p???0.05) have been found. To confirm the association of lung cancer with the mentioned polymorphisms, large number volunteers (patients and controls) will be required. 相似文献
15.
目的 探讨CYP3A4、CYP3A5在肺腺癌组织中的表达水平及与预后的相关性.方法 收集南京医科大学附属肿瘤医院胸外科87例肺腺癌病理组织及其对应的临床资料,病理标本制作组织芯片,通过免疫组化法明确组织芯片中C YP3 A4、CYP3A5蛋白的表达情况,结合临床病理特征和随访资料进行统计分析.结果 肺腺癌组织芯片的免疫组化结果显示,CYP3A4在肺腺癌组织中显著高表达,而其在癌旁正常组织中则显著低表达(P =0.012);肺腺癌中CYP3A4的表达水平与肺腺癌TMN分期(P=0.013)和肿瘤分化程度(P =0.044)相关.与之相反,CYP3A5在肺腺癌组织中的表达水平显著低于癌旁正常组织(P <0.001);肺腺癌中CYP3A5的表达与肺腺癌组织分化程度(P =0.013)显著相关.CYP3A4高表达患者总生存期和无瘤生存期较CYP3 A4低表达患者显著缩短(P<0.05),CYP3A5低表达患者总体生存期和无瘤生存期较CYP3A5高表达患者显著缩短(P<0.05);联合分析显示,CYP3A4高表达合并CYP3A5低表达的患者预后较其他患者差(P<0.05),COX多因素分析显示,CYP3A4高表达合并CYP3A5低表达为肺腺癌预后不良的独立危险因素.结论 CYP3A4高表达合并CYP3A5低表达是影响肺腺癌患者预后的独立危险因素;CYP3A4高表达合并CYP3A5低表达可作为预测肺腺癌预后的一个新靶标. 相似文献
16.
Puisset F Chatelut E Sparreboom A Delord JP Berchery D Lochon I Lafont T Roché H 《Cancer chemotherapy and pharmacology》2007,60(2):305-308
Background A study was conducted to evaluate prospectively the correlation between docetaxel clearance and pharmacokinetics of dexamethasone
previously obtained in 21 patients.
Patients and methods Dexamethasone pharmacokinetics were performed in 17 patients 24 h before docetaxel treatment as monochemotherapy. Dexamethasone
and docetaxel plasma concentrations were determined by HPLC methods. Determination of docetaxel unbound fraction in plasma
was performed using microequilibrium dialysis.
Results Significant correlation was observed between observed plasma docetaxel clearances (CLdocetaxel) and values predicted from dexamethasone plasma clearance (CLdexa), unbound plasma docetaxel fraction estimated from serum α1-acid glycoprotein level (fuα1–AAG), and hepatic metastasis status. However, after splitting of the prospective data set according to gender, no correlation
was observed for males (R2 = 0.08, NS, n = 10), then strong correlation was observed for females (R2 = 0.78, P < 0.01, n = 7). Multivariate analysis was performed from data obtained in the women included in the first study and those of this prospective
study (n = 18). Docetaxel CL was significantly correlated with CLdexa (P = 0.001) and fuα1–AAG (P = 0.01) according to the relationship (with ±95% confidence intervals): CLdocetaxel (l/h) = 1.92 (±0.94) × CLdexa (l/h) + 2.68 (±1.95) × fuα1–AAG (%) (R2 = 0.68).
Conclusion Dexamethasone may be used to predict docetaxel clearances in females, but not in males. 相似文献
17.
Ogasawara Ken Vince Bradley Xu Christine Zhang Meng Palmisano Maria Krishna Gopal 《Cancer chemotherapy and pharmacology》2020,85(5):995-1001
Cancer Chemotherapy and Pharmacology - Fedratinib, an oral, selective Janus kinase 2 inhibitor with activity against both wild-type and mutant Janus kinase 2, has pH-dependent solubility, with free... 相似文献
18.
Jean-Pascal Machiels Arthur Staddon Catherine Herremans Chi Keung Apexa Bernard Charles Phelps Nushmia Z. Khokhar Roland Knoblauch Trilok V. Parekh Luc Dirix Sunil Sharma 《Cancer chemotherapy and pharmacology》2014,74(4):729-737
Purpose
To evaluate the pharmacokinetics, safety and survival of trabectedin, metabolized primarily by cytochrome P450 (CYP)3A4 enzyme, when coadministered with rifampin (CYP3A4 inducer) or ketoconazole (CYP3A4 inhibitor) in adult patients with advanced solid tumors.Methods
Two phase 1/2a, 2-way crossover studies were conducted. For rifampin study, 12 patients were randomized (1:1) to sequence of a cycle of trabectedin (1.3 mg/m2, 3 h, i.v.) coadministered with rifampin (600 mg/day, 6-days), and a cycle of trabectedin monotherapy (1.3 mg/m2, 3 h, i.v.). In ketoconazole study, eight patients were randomized (1:1) to sequence of a cycle of trabectedin (0.58 mg/m2, 3 h, i.v.) coadministered with ketoconazole (200 mg, twice-daily, 15-doses), and a cycle of trabectedin monotherapy (1.3 mg/m2, 3 h, i.v.).Results
The systemic exposure (geometric means) of trabectedin was decreased [22 % (C max) and 31 % (AUClast)] with rifampin coadministration and increased [22 % (C max) and 66 % (AUClast)] with ketoconazole coadministration. This correlated with an increased clearance with rifampin (39.6–59.8 L/h) and a decreased clearance with ketoconazole (20.3–12.0 L/h). Consistent with earlier studies, the most common (≥40 %) treatment-emergent adverse events in both studies were nausea, vomiting, diarrhea, hepatic function abnormal, anemia, neutropenia, thrombocytopenia and leukopenia.Conclusions
Coadministration of rifampin or ketoconazole altered the pharmacokinetics of trabectedin, but no new safety signals were observed. Coadministration of trabectedin with potent CYP3A4 inhibitors or inducers should be avoided if possible. If coadministration of trabectedin with a strong CYP3A4 inhibitor is required, close monitoring for toxicities is recommended, so that appropriate dose reductions can be instituted as warranted. 相似文献19.
Gregory A Reed Jean M Sunega Debra K Sullivan John C Gray Matthew S Mayo James A Crowell Aryeh Hurwitz 《Cancer epidemiology, biomarkers & prevention》2008,17(10):2619-2624
We have completed a single ascending dose clinical study of the proposed chemopreventive agent 3,3'-diindolylmethane (DIM). The study agent was nutritional-grade, absorption-enhanced BioResponse 3,3'-diindolylmethane (BR-DIM). We determined the safety, tolerability, and pharmacokinetics of single doses of BR-DIM in drug-free, non-smoking, healthy men and women. Groups of four subjects were enrolled for each dose level. After randomization, one subject in each group received placebo whereas three received active BR-DIM. The doses administered were 50, 100, 150, 200, and 300 mg, with the 300-mg dose repeated in an additional group. No BR-DIM-related adverse effects were reported at doses up to 200 mg. At the 300-mg dose, one of six subjects reported mild nausea and headache and one also reported vomiting. Only the latter effect was judged as probably related to the study agent. Analysis of serial plasma samples showed that only one subject at the 50-mg dose had detectable concentrations of DIM. The single 100-mg dose of BR-DIM resulted in a mean maximum plasma concentration (C(max)) of 32 ng/mL and a mean area under the curve (AUC) of 128 h ng/mL, and a single 200-mg dose produced a mean C(max) of 104 ng/mL and a mean AUC of 553 h ng/mL. The single 300-mg dose of BR-DIM resulted in a mean C(max) of 108 ng/mL and a mean AUC of 532 h ng/mL. We conclude that BR-DIM is well tolerated at single doses of up to 200 mg, and that increasing the dose to 300 mg did not result in an increase in C(max). 相似文献
20.
Guilhaumou R Solas C Bourgarel-Rey V Quaranta S Rome A Simon N Lacarelle B Andre N 《Cancer chemotherapy and pharmacology》2011,68(6):1633-1638