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71.
Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan 总被引:36,自引:0,他引:36
Jonker JW Smit JW Brinkhuis RF Maliepaard M Beijnen JH Schellens JH Schinkel AH 《Journal of the National Cancer Institute》2000,92(20):1651-1656
BACKGROUND AND METHODS: Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin, and daunorubicin. To investigate the physiologic role of BCRP, we used polarized mammalian cell lines to determine the direction of BCRP drug transport. We also used the BCRP inhibitor GF120918 to assess the role of BCRP in protecting mice against xenobiotic drugs. Bcrp1, the murine homologue of BCRP, was expressed in the polarized mammalian cell lines LLC-PK1 and MDCK-II, and the direction of Bcrp1-mediated transport of topotecan and mitoxantrone was determined. To avoid the confounding drug transport provided by P-glycoprotein (P-gp), the roles of Bcrp1 in the bioavailability of topotecan and the effect of GF120918 were studied in both wild-type and P-gp-deficient mice and their fetuses. RESULTS: Bcrp1 mediated apically directed transport of drugs in polarized cell lines. When both topotecan and GF120918 were administered orally, the bioavailability (i.e., the extent to which a drug becomes available to a target tissue after administration) of topotecan in plasma was dramatically increased in P-gp-deficient mice (greater than sixfold) and wild-type mice (greater than ninefold), compared with the control (i.e., vehicle-treated) mice. Furthermore, treatment with GF120918 decreased plasma clearance and hepatobiliary excretion of topotecan and increased (re-)uptake by the small intestine. In pregnant GF120918-treated, P-gp-deficient mice, relative fetal penetration of topotecan was twofold higher than that in pregnant vehicle-treated mice, suggesting a function for BCRP in the maternal-fetal barrier of the placenta. CONCLUSIONS: Bcrp1 mediates apically directed drug transport, appears to reduce drug bioavailability, and protects fetuses against drugs. We propose that strategic application of BCRP inhibitors may thus lead to more effective oral chemotherapy with topotecan or other BCRP substrate drugs. 相似文献
72.
L. J. C. van Warmerdam W. W. ten Bokkel Huinink R. A. A. Maes J. H. Beijnen 《Journal of cancer research and clinical oncology》1994,120(7):427-433
Pharmacokinetic parameters of antineoplastic drugs are usually generated from concentration/time profiles obtained after multiple venipunctures. With limited-sampling models (LSM) this number can be reduced to between one and three timed plasma samples. LSMs may facilitate population pharmacokinetic/pharmacodynamic studies, which eventually may lead to a dosing strategy based on the characteristics of the individual patient. In this article, the development, validation and application of several LSMs reported in the literature are reviewed.Abbreviations LSM
limited-sampling model
- AUC
area under the concentration/time curve 相似文献
73.
L. J. van Warmerdam S. Rodenhuis E. van der Wall R. A. Maes J. H. Beijnen 《British journal of cancer》1996,73(8):979-984
The aim of this pharmacokinetic/pharmacodynamic study was to define the relationships of the carboplatin exposure with the toxicity in patients treated with high dose carboplatin (400 mg m-2 day-1), cyclophosphamide (1500 mg m-2 day-1) and thiotepa (120 mg m-2 day-1) for four consecutive days, followed by peripheral stem cell transplantation. Exposure to carboplatin was studied in 200 treatment days by measuring the area under the carboplatin plasma ultrafiltrate (pUF) concentration vs time curve (AUC). The AUC was obtained by using a previously validated limited sampling model. A total of 31 patients was studied who received one, two or three courses of this high-dose chemotherapy regimen. The unbound, plasma ultrafiltrate carboplatin was almost completely cleared from the body before each next treatment day in a course; the day-to-day AUC variation was 3.3%. The mean cumulative AUC over 4 days was 19.6 (range 14.1-27.2) mg ml-1 min-1. In 97 treatment days the carboplatin dose was calculated using the Calvert formula with the creatinine clearance as the measure for the glomerular filtration rate (GFR). For these courses, the inter-patient variability in pharmacokinetics was significantly reduced from 21% to 15% (P = 0.007) in comparison with the schemes where it was given as a fixed dose of 400 mg m-2. There were no relationships found between toxicity and the AUC of carboplatin, which may be due to the influence of overlapping toxicities of cyclophosphamide and thiotepa. However, the ototoxicity was strongly related to the cumulative carboplatin AUC. This toxicity was dose limiting for carboplatin in this schedule. It appeared that the carboplatin pharmacokinetics in these regimens were similar to those reported at conventional dosages. To reduce the inter-patient variation, the carboplatin dose can be calculated using the Calvert-formula with the creatinine clearance as the measure for the GFR. 相似文献
74.
Lingual thyroid gland: sonographic appearance 总被引:1,自引:0,他引:1
Thyroid dysgenesis is often manifested by a lingual or sublingual location of the thyroid gland. If radionuclide studies are not readily available or are contraindicated, ultrasound (US) may be used to locate the gland. The US appearance of a lingual thyroid gland and the role of US in the evaluation of suspected thyroid dysgenesis are described. 相似文献
75.
HPLC测定益肤霜中红霉素和地塞米松的含量 总被引:5,自引:0,他引:5
采用HPLC测定益肤霜中红霉素和地塞米松的含量,控制制剂的质量。色谱条件:固定相为Kromasil C18柱;流动相为乙腈-0.2mol/L醋酸铵-水,流速0.8ml/min;检测波长215nm。以c对峰面积A作直线回归,红霉素在1.5-24g/L地塞米松在20-300mg/L的范围内,其浓度与峰面积呈直线关系。红霉素回收率为99.69%;地塞米松的回收率为100.28%。本法操作简便,结果准确, 相似文献
76.
77.
Concepts necessary to an understanding of the basics of quality assurance audits are presented. Included are specific examples that bridged theory and practice by applying the protocol to a real-life diagnostic imaging situation. This method meets the present requirements of the Joint Commission of the Accrediation of Hospitals. 相似文献
78.
79.
80.
de Jonge ME Huitema AD van Dam SM Rodenhuis S Beijnen JH 《Therapeutic drug monitoring》2005,27(6):756-765
The anticancer prodrug cyclophosphamide (CP) is activated by the formation of 4-hydroxycyclophosphamide (4OHCP), which decomposes into phosphoramide mustard (PM). This activation pathway is inhibited by thiotepa. CP is inactivated by formation of 2-dechloroethylcyclophosphamide (2DCECP). The aim of this study was to develop a population pharmacokinetic model describing the complex pharmacokinetics of CP, 4OHCP, 2DCECP, and PM when CP is administered in a high-dose combination with thiotepa and carboplatin. Patients received a combination of CP (1000-1500 mg/m/d), carboplatin (265-400 mg/m/d), and thiotepa (80-120 mg/m/d) administered in short infusions over 4 days. Twenty blood samples were collected per patient per course. Concentrations of CP, 4OHCP, 2DCECP, PM, thiotepa, and tepa were determined in plasma. Using NONMEM, an integrated population pharmacokinetic model was used to describe the pharmacokinetics of CP, 4OHCP, 2DCECP, and PM, including the already described processes of autoinduction of CP and the interaction with thiotepa. Data were available on 35 patients (70 courses). The pharmacokinetics of CP were described with a 2-compartment model, and those of 4OHCP, 2DCECP, and PM with 1-compartment models. Before onset of autoinduction, it was assumed that CP is eliminated through a noninducible pathway accounting for 20% of total CP clearance, whereas 2 inducible pathways resulted in formation of 4OHCP (75%) and 2DCECP (5%). It was assumed that 4OHCP was fully converted to PM. Induction of CP metabolism was mediated by 2 hypothetical amounts of enzyme whose quantities increased in time in the presence of CP (kenz=0.0223 and 0.0198 hours). Induction resulted in an increased formation of 4OHCP (approximately 50%), PM (approximately 50%), and 2DCECP (approximately 35%) during the 4-day course, and concomitant decreased exposure to CP (approximately 50%). The formation of 2DCECP was not inhibited by thiotepa. Apparent volumes of distribution of CP, PM, and 2DCECP could be estimated being 43.7, 55.5, and 18.5 L, respectively. Exposure to metabolites varied up to 9-fold. The complex population pharmacokinetics of CP, 4OHCP, 2DCECP, and PM in combination with thiotepa and carboplatin has been established and may form the basis for further treatment optimization with this combination. 相似文献