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1.
《Drug metabolism and pharmacokinetics》2020,35(1):56-70
Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CLh) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CLh involving OATP1B-mediated hepatic uptake. CLh can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CLh and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction. 相似文献
2.
Sandrine F. Chebekoue 《Journal of occupational and environmental hygiene》2019,16(4):308-319
This study aimed at deriving occupational thresholds of toxicological concern for inhalation exposure to systemically-acting organic chemicals using predicted internal doses. The latter were also used to evaluate the quantitative relationship between occupational exposure limit and internal dose. Three internal dose measures were identified for investigation: (i) the daily area under the venous blood concentration vs. time curve, (ii) the daily rate of the amount of parent chemical metabolized, and (iii) the maximum venous blood concentration at the end of an 8-hr work shift. A dataset of 276 organic chemicals with 8-hr threshold limit values-time-weighted average was compiled along with their molecular structure and Cramer classes (Class I: low toxicity, Class II: intermediate toxicity, Class III: suggestive of significant toxicity). Using a human physiologically-based pharmacokinetic model, the three identified dose metrics were predicted for an 8-hr occupational inhalation exposure to the threshold limit value for each chemical. Distributional analyses of the predicted dose metrics were performed to identify the percentile values corresponding to the occupational thresholds of toxicological concern. Also, simple linear regression analyses were performed to evaluate the relationship between the 8-hr threshold limit value and each of the predicted dose metrics, respectively. No threshold of toxicological concern could be derived for class II due to few chemicals. Based on the daily rate of the amount of parent chemical metabolized, the proposed internal dose-based occupational thresholds of toxicological concern were 5.61?×?10?2 and 9?×?10?4 mmol/d at the 10th percentile level for classes I and III, respectively, while they were 4.55?×?10?1 and 8.5?×?10?3 mmol/d at the 25th percentile level. Even though high and significant correlations were observed between the 8-hr threshold limit values and the predicted dose metrics, the one with the rate of the amount of chemical metabolized was remarkable regardless of the Cramer class (r2 = 0.81; n = 276). The proposed internal dose-based occupational thresholds of toxicological concern are potentially useful for screening-level assessments as well as prioritization within an integrated occupational risk assessment framework. 相似文献
3.
《Drug metabolism and pharmacokinetics》2019,34(1):87-94
The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with Ki values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with Km values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CLR) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CLR (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CLR of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates. 相似文献
4.
用有机锗(Ge-132)试验治疗荷移植肝癌小鼠。结果:De-132高剂量(12.5mg/次)治疗组的抑癌率为用31.0%,移植肝癌白细胞(WBC)浸润(+++)占72.7%、血清超氧化物歧化酶(SOD)活性为121Nu/ml,而生理盐水对照治疗组相应的后两项指标分别为用36.4%及81Nu/ml,两组比较有显著性差异(P<0.05);环磷酰胺(CTX)治疗组的抑癌率为37.0%,癌体WBC浸润(+++)为27.3%,血清SOD活性为102Nu/ml;ge-132高剂量与CTX2联合治疗组的抑癌率为45.0%,癌体WBC浸润(+++)为54.5%,血清SOD活性为142Nu/ml,两组比较,后二项指标有显著性差异(P<0.05)。由此提示Ge-132高剂量能明显增强荷移植肝癌小鼠的细胞免疫及血清SOD活性,并有一定的抗移植肝癌作用。 相似文献
5.
Occupational hydrocarbon exposure and chronic nephropathy 总被引:2,自引:0,他引:2
P. Hotz 《Toxicology》1994,90(3):163-283
This review aims at discussing the questions raised by the hydrocarbon-related chronic nephropathy and its possible consequence, the hydrocarbon-related chronic renal failure. It has been attempted to adopt the point of view of the clinician. Therefore, the most important part of the review is devoted to a presentation and an analysis of the available data on humans. The main features of the available studies on human subjects are presented, their conclusions discussed in the light of the possible methodological flaws, and practical conclusions drawn. After a discussion of the main difficulties encountered for selecting the suitable exposure indicator, the studies are discussed in order of decreasing quality of the study design (cohort, case-control, cross-sectional studies, and the case reports). It is concluded that a great deal of controversies about chronic hydrocarbon-related nephropathy is explained by differences in the study design and that hydrocarbon-induced nephropathy is probably more than a mere hypothesis, although a causal relationship has not yet been proven. Finally, some practical consequences for dealing with a hydrocarbon-exposed patient diagnosed with a kidney disease and the need for further research are discussed. 相似文献
6.
饮水有机浓集物致突变活性影响因素的研究 总被引:4,自引:0,他引:4
本文探讨饮水有机物浓集流速及加氯量对致突变活性的影响。试验表明,饮水有机物浓集流速控制在每分钟2倍树脂柱床体积时,可获得最佳致突变效果。当加氯量≥20mg/L时,对TA98±S9和TA100—S9菌株有致突变活性,≤2mg/L时对TA98±S9和TA100±S9菌株无致突变活性。为最大限度减少致突变效应,在净水过程中保证流行病学安全前提下,减少加氯量和加氯次数是十分必要的。 相似文献
7.
白洋淀上游蓄污工程沿岸地下水污染状况及对居民健康影响的调查 总被引:2,自引:0,他引:2
(Investig ative Group on Hygienic Status of Drinking Water in Bai Yang Dian Hebei Province) 《环境与健康杂志》1994,11(1):3-5
白洋淀污染一直是国家和河北省所关注的问题,对白洋淀上游蓄污工程沿岸小环境调查表明;饮用深层地下水受到城市工业废水的污染,主要污染物为有机物。污染区儿童贫血率、白细胞计数、舒张压高于非污染区,白细胞吞噬率低于非污染区,居民恶性肿瘤标化死亡比高于非污染区,肝癌标化死亡比明显上升。 相似文献
8.
We have reviewed some of the factors which contribute to lung damage by various toxicants. These include disposition of the chemical, its metabolism, individual cell type susceptibility and the potential for the tissue to repair. We have discussed the use of biochemical parameters to measure the functional activity of individual cell types in order to predict the damage to specific cell types and concluded that careful morphological analysis of lung tissue is likely to provide a more sensitive and informative measure of specific cell type injury. However, in order to investigate the mechanism of toxicity of pulmonary toxicants it is essential to establish the primary biochemical event that leads to cell damage and morphological change. The importance of separating the relevant biochemical change(s) from the cascade of biochemical events associated with dead and dying cells and the reparative response of the lung is emphasised.This report results from a discussion sponsored and organised by the Advisory Subgroup in Toxicology (AST) of the European Science Foundation's Standing Committee for the European Medical Research Councils and held at the Medical Research Council Toxicology Unit, Carshalton, U. K. Those taking part were: W. N. Aldridge (AST; as above); J. Bignon (Unit for Research in Renal and Pulmonary Pathology, University of Paris, Creteil, France); P. H. Burri (Section of Developmental Biology, Institute of Anatomy, University of Berne, Switzerland); G. M. Cohen (as above); D. Dinsdale (MRC Toxicology Unit, Carshalton U. K.); P. Hedqvist (Dept. of Physiology, Karolinska Institute, Stockholm, Sweden); D. Henschler (AST; Dept. of Toxicology and Pharmacology, University of Wurzburg, FDR); G. J. Laurent (Biochemistry Unit, Cardiothoracic Institute, University of London, London, U. K.); R. Lauwerys (AST Industrial and Medical Toxicology Unit, University of Louvain, Brussels, Belgium); F. Lembeck (AST; Dept. for Experimental and Clinical Pharmacology, University of Graz, Austria); N. Lery (AST; Poison Control Centre, Lyon, France); P. Moldeus (Dept. of Forensic Medicine, Karolinska Institute, Stockholm, Sweden); B. Nemery (MRC Toxicology Unit, Carshalton, U. K.); A. Saria (Dept. for Experimental and Clinical Pharmacology, University of Graz, Austria); L. L. Smith (as above);B. Terracini (AST; Dept. of Pathology and Cancer Epidemiology, University of Turin, Italy) 相似文献
9.
<正>病理技术是病理学的重要组成部分,并广泛应用于临床和科研工作中。病理制片的质量直接影响着病理诊断的准确性,为保证病理医师的诊断准确,结合20余年实际工作经验,谈谈做好病理组织切片的体会。 相似文献
10.
为探讨职业性接触苯、甲苯、二甲苯对子代行为的影响,以46名父母生育期接触苯、甲苯、二甲苯的儿童为暴露组;抽取与暴露组同年龄、同性别、同班级、其父母无任何职业有害因素接触史的58名儿童为对照组,用WICS-R(韦克斯勒儿童智力量表)对研究对象进行智力测验,用NB-I型视运动反应仪测试视简单反应时。结果显示,接触组各智力测验的得分均低于对照组,视反应时指标慢于对照组,差异有显著意义;进一步的分层分析结果显示,母接触组的各项得分均低于对照组,而父接触组的各项得分与对照组之间差异无显著意义。 相似文献