Cellular Level Transport

Simple Diffusion Linea/No Competition Concentration Gradient 

Facilitated Diffusion Saturcftlon/Compefflfon Concentration Gradient 

Primary Active Transport SaturaHon/Carnpelttton ATP Hydrolysis 

Secondary Active Transport Satu ratio rVCom petition lon/Metaboffle Gradient 

For transporters, relatively low protein expression level and limited transport capacity makes for nonlinear, enzyme-like transport kinetics that is, the transport rate saturates with increasing substrate concentration. This phenomenon is the basis for the competitive interactions generally found for chemicals that are handled by one or more common transporters this is usually manifest as inhibition of the transport of one chemical by a structural analog. The extent to which these competitive interactions are important depends on the concentrations of the chemicals involved, their relative affinities for the common transporter, and their phar-macological/toxicological profiles (effects, effective concentrations, therapeutic index). Competition for transport is discussed below in the context of drug-drug interactions. 

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Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by pre 3 HDL binding to the ABC-1 transporter protein via apo A-l. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol CE, cholesteryl ester PL, phospholipid ACAT, acyl-CoA cholesterol acyltransferase LCAT, lecithinicholesterol acyltransferase A-l, apolipoprotein A-l LDL, low-density lipoprotein VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

An appropriate starting point for any discussion of drug transport in the gastrointestinal (GI) tract at the cellular level requires some introductory remarks on the structure and function of GI tissue. As a class of tissue, epithelia demarcate body entry points (skin, eye, respiratory, urinary, and GI organ systems), predisposing a general barrier function with respect to solute entry and translocation. In addi-... 

The coupling of solute transport in the GI lumen with solute lumenal metabolism (homogeneous reaction) and membrane metabolism (heterogeneous reaction) has been discussed by Sinko et al. [54] and is more generally treated in Cussler s text [55], At the cellular level, solute metabolism can occur at the mucosal membrane, in the enterocyte cytosol, and in the endoplasmic reticulum (or microsomal compartment). For peptide drugs, the extent of hydrolysis by lumenal and membrane-bound peptidases reduces drug availability for intestinal absorption [56], Preferential hydrolysis (metabolic specificity) has been targeted for reconversion... 

At the cellular level, the various types of receptor, transporter, enzyme and ion charmel are all chiral in form. Thus although the enantiomers of a drug may have identical physicochemical properties, the way in which they may interact with chiral targets at the level of the cell will give rise to different pharmacod)mamic and pharmacokinetic properties. A few simple examples will illustrate how taste and olfactory receptors can differentiate between enantiomers. Thus R-carvone tastes like spearmint whereas the S-isomer tastes like caraway. Similarly, R-limolene smells like lemon whereas the S-enantiomer tastes of orange. 

It is tempting to speculate that the next comprehensive examination of hemopexin-mediated heme transport will have exciting new sections devoted to the molecular properties of MHBP and the hemopexin receptor, to the mechanism of heme release from hemopexin, to new intracellular heme transport partners, and to the links provided by the hemopexin system among heme, iron, and copper at the cellular level. 

At the cellular level, plant secondary metabolites have five major effects on herbivores (a) alteration of DNA replication, RNA transcription, and protein synthesis (b) alteration of membrane transport processes (c) enzyme inhibition and activation (d) blocking of receptor sites for endogenous chemical transmitters and (e) affecting the conformation of other macromolecules (Robinson, 1979). 

At the cellular level, rotenone inhibits cellular respiration by blocking electron transport between flavoprotein and ubiquinone. It also inhibits spindle microtubule assembly. ... 

GSH is not transported into cells. For circulating GSH to increase intracellular GSH concentrations, it must first be hydrolyzed to Glu and CysGly, which are subsequently transported into the cell and serve as substrates for GSH synthesis. Thus, GSH administered orally or parenterally, and that produced by the liver and released into the circulation enhance tissue levels of GSH by providing a source of its constituent amino acids. In contrast, GSH monoesters, which are well absorbed after oral administration, as is GSH, are readily transported to cells and then hydrolyzed to GSH and the corresponding alcohol. Thus, higher cellular levels of GSH result from oral administration of GSH monoesters than from oral administration of comparable doses of GSH. 

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