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1.
The kinetics of substrate removal by the liver and the resulting nonlinear changes in unbound fraction along the flow path at varying input drug concentrations were examined by a model simulation study. Specifically, we varied the binding association constant, KA, and the Michaelis-Menten constants (Km and Vmax) to examine the steady state drug removal (expressed as hepatic extraction ratio E) and changes in drug binding for (i) unienzyme systems and (ii) simple, parallel metabolic pathways; zonal metabolic heterogeneity was also added as a variable. At low KA, E declined with increasing input drug concentration, due primarily to saturation of enzymes; only small differences in binding were present across the liver. At high KA, a parabolic profile for E with concentration was observed; changes in unbound fraction between the inlet and the outlet of the liver followed in parallel fashion. Protein binding was the rate-determining step at low input drug concentrations, whereas enzyme saturation was the rate-controlling factor at high input drug concentration. Heterogeneous enzymic distribution modulated changes in unbound fraction within the liver and at the outlet. Despite marked changes in unbound fraction occurring within the liver for different enzymic distributions, the overall transhepatic differences were relatively small. We then investigated the logarithmic average unbound concentration and the length averaged concentration as estimates of substrate concentration in liver in the presence of nonlinear drug binding. Fitting of simulated data, with and without assigned random error (10%), to the Michaelis-Menten equation was performed; fitting was repeated for simulated data obtained with presence of a specific inhibitor of the high-affinity, anteriorly distributed pathway. Results were similar for both concentration terms: accurate estimates were obtained for anterior, high affinity pathways; an overestimation of parameters was observed for the lower affinity posteriorly distributed pathways. Improved estimations were found for posteriorly distributed pathways upon inhibition with specific inhibitors; with added random error, however, the improvement was much decreased. We applied the method for fitting of several sets of metabolic data obtained from rat liver perfusion studies performed with salicylamide (SAM) (i) without and (ii) with the presence of 2,6-dichloro-4-nitrophenol (DCNP), a SAM sulfation inhibitor. The fitted results showed that SAM sulfation was a high-affinity high-capacity pathway; SAM glucuronidation was of lower affinity but comparable capacity as the sulfation pathway, whereas SAM hydroxylation was of lower affinity and lower capacity. 相似文献
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珠江口盆地开平凹陷油气聚集条件分析 总被引:2,自引:0,他引:2
珠江口盆地自新生代以来,曾先后受到不同方向张应力的作用,造成了不同时期构造体系的交叉叠合.中中新世以来构造运动强烈,并具有东强西弱的特点,对油气的运移与聚集产生了重要影响.开平凹陷的剧烈断裂和断陷活动始于始新世,并在同期沉积了巨厚的文昌组.晚渐新世以后,由于断裂活动非常微弱,在成熟的烃源岩与其上地层之间缺乏有效的油源断层,因而自生自储、近距离运移可能是开平凹陷油气聚集的基本特征.在凹陷内部,因重力滑动和欠压实泥岩共同作用所形成的KPll-1构造带可能是该区最具有油气远景的地区. 相似文献
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FV Elmslie M Rees MP Williamson M Kerr MJ Kjeldsen KA Pang A Sundqvist ML Friis D Chadwick A Richens A Covanis M Santos A Arzimanoglou CP Panayiotopoulos D Curtis WP Whitehouse RM Gardiner 《Canadian Metallurgical Quarterly》1997,6(8):1329-1334
The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied. 相似文献
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鲁布革水电厂原R30计算机监控系统更新改造过程中,重点研究了与原西门子RTU的数据交换,机组功率调节和线路定功率调节的实现有关问题,在对3号机组计算机监控系统改造试验的基础上,成功地实现了计算机监控系统的整体改造,改造后采用的国产NARISSJ-3000计算机监控系统实用可靠,功能完善,配置灵活,具有国际,国内领先水平。 相似文献
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D Pang 《Canadian Metallurgical Quarterly》1995,6(2):243-257
The embryogenesis, closure technique, and preoperative preparation of open myelomeningocele are described in this article. Both early and late complications of myelomeningocele closure are discussed with respect to predisposing factors, diagnosis, treatment, and prevention. These complications include worsened neurological level, wound dehiscence, wound infection, cerebrospinal fluid leak, postoperative ileus, symptomatic Chiari malformation, shunt infection, necrotizing enterocolitis, and problems related to kyphectomy. 相似文献