一级并行米氏消除动力学的平均稳态浓度及最佳剂量方案

大多数药物在有效治疗血药浓度范围内,呈一级消除动力学。但有的药物如苯妥英钠、水杨酸盐等,其消除动力学表现为Michaelis-Menten动力学(简称米氏动力学)或一级并行米氏动力学。在临床药物治疗中,一般需多次给药,使血药浓度达到稳态并维持在有效、安全的水平上     

静注一级并行米氏消除动力学的稳定浓度

对静注一级并行米氏消除动力学模型,导出了稳态浓度（最大值、平均值和最小值）精确值和近似值的计算公式,并讨论了平均稳态浓度与AUC/τ的关系,给出了一次给药即可达到稳态浓度的给药方案．     

应用药物动力学评价按(一级并行)米氏过程消除药物的给药方案:静脉点滴

本文讨论符合（一级并行）米氏消除药物的多剂量静脉点滴给药的给药方案评价方法并给出了应用例子。     

静注和静滴米氏消除动力学参数估计

在非线性药物动力学中,Michaelis-Menten消除动力学(以下简称米氏动力学)和一级并行米氏动力学是最常见的两种,本文就这两种情况,给出一种估计静注和静滴动力学参数的方法——替换法。     

按(一级并行)米氏过程消除药物的稳态性质分析的数值解法

本文讨论消除符合（一级并行）米氏过程药物的多剂量周期性血管外或血管内给药稳态性质分析的数值解法。     

基于SVM 的药物靶点预测方法及其应用

目的:基于已知药物靶点和潜在药物靶点蛋白的一级结构相似性,结合SVM技术研究新的有效的药物靶点预测方法。方法:构造训练样本集,提取蛋白质序列的一级结构特征,进行数据预处理,选择最优核函数,优化参数并进行特征选择,训练最优预测模型,检验模型的预测效果。以G蛋白偶联受体家族的蛋白质为预测集,应用建立的最优分类模型对其进行潜在药物靶点挖掘。结果:基于SVM所建立的最优分类模型预测的平均准确率为81.03%。应用最优分类器对构造的G蛋白预测集进行预测,结果发现预测排位在前20的蛋白质中有多个与疾病相关。特别的,其中有两个G蛋白在治疗靶点数据库(TTD)中显示已作为临床试验的药物靶点。结论:基于SVM和蛋白质序列特征的药物靶点预测方法是有效的,应用该方法预测出的潜在药物靶点能够为发现新的药靶提供参考。     

吸入麻醉诱导阶段药物动力学模型的定量分析

考虑了给药浓度、氧流量对吸入麻醉诱导阶段的影响,建立了诱导期药物动力学模型.利用非线性拟合的方法给出了诱导阶段的麻醉药血药浓度的拟合曲线;讨论了给药浓度相同的情况下,氧流量对诱导阶段所需时间的影响,得到了诱导阶段的氧流量分别与吸入肺部的药物浓度和体内消除系数的关系式,利用这两个关系式和诱导阶段的一般解可确定在此阶段体内血药浓度和完成诱导的时间.     

氟苯尼考及氟苯尼考胺在克氏原螯虾体内药物代谢动力学

研究不同给药方式下,氟苯尼考及其代谢产物氟苯尼考胺在克氏原螯虾体内的药动学特征。在水温为(21±1)℃条件下,分别给予20 mg/kg体重单剂量血窦注射或50 mg/kg体重单剂量口灌给药,并于0.083、0.25、0.5、1、2、3、4、6、8、12、18、24和36h时间点采集血淋巴,运用反相色谱法检测血淋巴中氟苯尼考及氟苯尼考胺的浓度,采用3p97软件的非房室模型统计矩方法分析药时数据。结果表明:血窦给药后,氟苯尼考的消除半衰期(t1/2)、表观分布容积[Vd(ss)]、总体清除率(CL)分别为8.26h、14.43 L/kg、1.21 L/kg.h,氟苯尼考胺消除半衰期和代谢率(MR)分别为20.28h、9.3%;口灌给药后,氟苯尼考达峰浓度(Cmax)、达峰时间(Tmax)、消除半衰期、生物利用度(F)分别为2.49 mg/kg、1.0h、10.01h、21.6%,氟苯尼考胺的消除半衰期和代谢率分别为16.0h、37.5%。氟苯尼考在克氏原螯虾体内的消除比氟苯尼考胺快,并能广泛地分布于身体各组织中;氟苯尼考在胃肠中吸收迅速,但其生物利用度不高,代谢率低。     

烟酸诺氟沙星在松浦镜鲤体内的药动学特征

结合单纯聚集法和二步法,应用高效液相色谱(HPLC)技术研究了分别以10、30、60 mg/kg剂量对松浦镜鲤(Cyprinus carpio specularis)口灌烟酸诺氟沙星后,药物在实验鱼血浆中的药动学特征。3种给药剂量下,诺氟沙星在松浦镜鲤血浆中的血药浓度和时间关系均可用一级吸收二室开放模型进行描述,吸收半衰期(t1/2ka)分别为0.165、0.061、0.043 h,消除半衰期(t1/2β)分别为18.282、29.969、42.051 h,达峰时间(Tmax)分别为0.333、0.327、0.302 h,达峰浓度(Cmax)分别为4.780、6.247、12.689 mg/L,药时曲线下面积(AUC)分别为32.698、53.015、174.998 mg·h/L,表观分布容积(Vd)分别为1.044、4.347、4.561 L/kg。说明随着给药剂量的增加,诺氟沙星的吸收和消除速率均加快,给药剂量对药动学特征有显著影响。     

蛋白质药物口服的研究进展

蛋白质药物口服给药系统因其给药方便、顺应性好,逐渐成为一种最有前景的给药方式.从提高蛋白质药物生物利用度入手,综述采用结构修饰、吸收促进剂、酶抑制剂、结肠定位释药、脉冲式药物给药系统和受体介导靶向载体系统等方式,均可大大提高蛋白质药物的口服生物利用度和在胃肠道中的稳定性.     

Periodic operation of bioreactors for autocatalytic reactions with Michaelis-Menten kinetics

The performance of an isothermal tubular bioreactor carrying out autocatalytic reactions obeying Michaelis-Menten Kinetics is analyzed for improvement in the average yield of product B. Under steady-state condition, the reactor is shown to exhibit input multiplicities in the yield of B with the mean residence time. Simulation results show that a significant improvement in the average yield of B is obtained under feed substrate concentration cycling. The two values of mean residence time giving identical yield under conventional steady-state operation is shown to give distinctly different behaviour under periodic operation. The lower value of the residence time gives improved average yield of B. The performances of the reactor with power law kinetics and that with the Michaelis-Menten kinetics show distinct average yield under periodic operation even though steady-state operation gives identical yield.     

Time-dependent elimination of substrates flowing through the liver or kidney

Established steady-state models of elimination of flowing substrates by Michaelis-Menten kinetics in the intact liver and kidney are extended to time-dependent situations. It is shown how time-dependent distributions of substrate concentration can be calculated using steady-state results and a knowledge of the motion of fluid through the organs. The result is simplest when time-dependence is due to changes in substrate concentrations at the inlet, for example following injection or infusion. The case of the liver is treated in greater detail, and includes an evaluation of the instantaneous overall elimination rate.     

Kinetics of oral propylene glycol-induced acute hyperlactatemia

The kinetics of PD-induced HL in rat have been investigated. The data obtained indicated that PD was solely responsible for the elevation (1.83- to 4.01-fold) of blood lactate that was sustained long enough to affect considerably the normal physiological function of the system. The production of lactate increased as the dose of PD increased up to 38.66 mmole/kg, thereby obeying the Michaelis-Menten kinetics model that gave an apparent Km and Vmax as 7.14 mmole/kg and 7.50 mmole/liter/hr, respectively. The t1/2 elimination time ranged from 1.40 to 5.82 hr which followed apparent first-order kinetics. Pyrazole inhibited (Ki = 6 mumole/kg) the PD-induced HL competitively, suggesting that alcohol dehydrogenase might have played a regulatory role in the conversion of PD to lactate. The PD-induced HL in rat and the LA in human patients are two distinct biochemical entities; reasoning has been given to substantiate that HL is lower order LA. Evidence has been presented to show that PD is a suitable and effective potential agent for producing experimental HL in rat in preference to agents that are currently being used.     

On the relation between extended forms of the sinusoidal perfusion and of the convection-dispersion models of hepatic elimination

Two models of hepatic elimination, the distributed sinusoidal perfusion model, and the convection-dispersion model, are extended and then compared for first order kinetics in the steady-state. The sinusoidal perfusion model is extended by the inclusion of intrahepatic sites of mixing between sinusoids. The degree of such mixing is estimated for taurocholate elimination by isolated perfused rat livers by a comparison of anatomical and kinetic estimates of uptake heterogeneity, using previously published data. The dispersion model is generalized by the inclusion of distributions of enzyme activity along the flow. Direct comparison of the two models in the limit in which the degree of dispersion is small, allows the flow-dependence of the dispersion coefficient to be determined, thereby greatly extending the explanatory power of the convection-dispersion model. Finally, the effect of intrahepatic mixing sites on uptake by Michaelis-Menten kinetics is quantified in terms of the distributed sinusoidal perfusion model, with results which may be applicable to capillary beds in general.     

Steady-State Cerebral Glucose Concentrations and Transport in the Human Brain

Abstract: Understanding the mechanism of brain glucose transport across the blood-brain barrier is of importance to understanding brain energy metabolism. The specific kinetics of glucose transport have been generally described using standard Michaelis-Menten kinetics. These models predict that the steady-state glucose concentration approaches an upper limit in the human brain when the plasma glucose level is well above the Michaelis-Menten constant for half-maximal transport, K _t. In experiments where steady-state plasma glucose content was varied from 4 to 30 m M , the brain glucose level was a linear function of plasma glucose concentration. At plasma concentrations nearing 30 m M , the brain glucose level approached 9 m M , which was significantly higher than predicted from the previously reported K _t of ∼4 m M ( p < 0.05). The high brain glucose concentration measured in the human brain suggests that ablumenal brain glucose may compete with lumenal glucose for transport. We developed a model based on a reversible Michaelis-Menten kinetic formulation of unidirectional transport rates. Fitting this model to brain glucose level as a function of plasma glucose level gave a substantially lower K _t of 0.6 ± 2.0 m M , which was consistent with the previously reported millimolar K _m of GLUT-1 in erythrocyte model systems. Previously reported and reanalyzed quantification provided consistent kinetic parameters. We conclude that cerebral glucose transport is most consistently described when using reversible Michaelis-Menten kinetics.     

Optimum design of a series of CSTRs performing reversible Michaelis-Menten kinetics: a rigorous mathematical study

The optimum design of a given number of CSTRs in series performing reversible Michaelis-Menten kinetics in the liquid phase assuming constant activity of the enzyme is studied. In this study, the presence of product in the feed stream to the first reactor, as well as the effect of the product intermediate concentrations in the downstream reactors on the reaction rate are investigated. For a given number of N CSTRs required to perform a certain degree of substrate conversion and under steady state operation and constant volumetric flow rate, the reactor optimization problem is posed as a constrained nonlinear programming problem (NLP). The reactor optimization is based on the minimum overall residence time (volume) of N reactors in series. When all the reactors in series operate isothermally, the constrained NLP is solved as an unconstrained NLP. And an analytical expression for the optimum overall residence time is obtained. Also, the necessary and sufficient conditions for the minimum overall residence time of N CSTRs are derived analytically. In the presence of product in the feed stream, the reversible Michaelis-Menten kinetics shows competitive product inhibition. And this is, because of the increase in the apparent rate constant K^' _m that results in a reduction of the overall reaction rate. The optimum total residence time is found to increase as the ratio (‚₀) of product to substrate concentrations in the feed stream increases. The isomerization of glucose to fructose, which follows a reversible Michaelis-Menten kinetics, is chosen as a model for the numerical examples.     

Evaluation of the effectiveness factor along immobilized enzyme fixed-bed reactors: Design of a reactor with naringinase covalently immobilized into glycophase-coated porous glass

A design equation is presented for packed-bed reactors containing immobilized enzymes in spherical porous particles with internal diffusion effects and obeying reversible one-intermediate Michaelis-Menten kinetics. The equation is also able to explain irreversible and competitive product inhibition kinetics. It allows the axial substrate profiles to be calculated and the dependence of the effectiveness factor along the reactor length to be continuously evaluated. The design equation was applied to explain the behavior of naringinase immobilized in Glycophase-coated porous glass operating in a packed-bed reactor and hydrolyzing both p-nitrophenyl-alpha-L-rhamnoside and naringin. The theoretically predicted results were found to fit well with experimentally measured values.