Carrier-mediated transport active

Carrier-mediated transport, Active Efflux, Passive (trans and para cellular) diffusion... 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

Figure 1 General pathways through which molecules can actively or passively cross a monolayer of cells. (A) Endocytosis of solutes and fusion of the membrane vesicle with the opposite plasma membrane in an active process called transcytosis. (B) Similar to A, but the solute associates with the membrane via specific (e.g., receptor) or nonspecific (e.g., charge) interactions. (C) Passive diffusion between the cells through the paracellular space. (C, C") Passive diffusion (C ) through the cell membranes and cytoplasm or (C") via partitioning into and lateral diffusion within the cell membrane. (D) Active or carrier-mediated transport of an otherwise poorly membrane permeable solute into and/or out of a cellular barrier.

Several attempts have been made to estimate the dose required in humans in relation to a drug s potency, and to put this into the context of solubility and permeability for an optimal oral drug [2, 3]. A relatively simple example of this is where a 1.0 mg kg-1 dose is required in humans, then 52 pg mL"1 solubility is needed if the permeability is intermediate (20-80%) [3]. This solubility corresponds approximately to 100 pM of a compound with a MW of 400 g mol-1. Most screening activities for permeability determinations in, e.g., Caco-2, are made at a concentration of 10 pM or lower due to solubility restrictions. The first implication of this is that the required potency for these compounds needs to correspond to a dose of <0.1 mg kg-1 in humans if the drug should be considered orally active. Another implication would be the influence of carrier-mediated transport (uptake or efflux), which is more evident at low concentrations. This could result in low permeability coefficients for compounds interacting with efflux transporters at the intestinal membrane and which could either be saturated or of no clinical relevance at higher concentrations or doses. 

Lastly, pharmacogenomics could provide new tools for the design of more specific and active CNS pharmaceuticals. The efficacy of a broad spectrum of neuro-pharmaceutical drugs is often complicated by their inability to reach their site of action because of the BBB. One way to overcome this is to use carrier-mediated transport at the luminal and/or abluminal membranes of the endothelial cells of the BBB. This will provide a physiologically based drug delivery strategy for the brain by designing new chemical entities or fused proteins that can cross the BBB via these transporters. 

Depending upon the mechanism that is employed by the organism to accumulate the solute, internalisation fluxes can vary both in direction and order of magnitude. The kinetics of passive transport will be examined in Section 6.1.1. Trace element internalisation via ion channels or carrier-mediated transport, subsequent to the specific binding of a solute to a transport site, will be addressed in Section 6.1.2. Finally, since several substances (e.g. Na+, Ca2+, Zn2+, some sugars and amino acids) can be concentrated in the cell against their electrochemical gradient (active transport systems), the kinetic implications of an active transport mechanism will be examined in Section 6.1.3. Further explanations of the mechanisms themselves can be obtained in Chapters 6 and 7 of this volume [24,245]. 

Transport across the cell membrane may occur via different routes. Some of these transport processes are energy dependent and therefore termed active others are independent from energy, thus passive. Passive transport phenomena, for example, transcellular transport, are triggered by external driving forces, such as concentration differences, and do not require metabolic activity. However, generally, they are restricted to small lipophilic compounds. In contrast, active transport phenomena, such as active carrier-mediated transport or vesicular pathways, take course independent from external driving... 

However, substances with physico-chemical characteristics that are not favorable for absorption could still reach the systemic circulation because specific mechanisms exist to enable, e.g., dietary fats and electrolytes to be absorbed. Occasionally a substance may be sufficiently similar to a nutrient substance to compete with that nutrient for a carrier mediated or active transport... 

The most efficient rectal absorption enhancers, which have been studied, include surfactants, bile acids, sodium salicylate (NaSA), medium-chain glycerides (MCG), NaCIO, enamine derivatives, EDTA, and others [45 17]. Transport from the rectal epithelium primarily involves two routes, i.e., the paracellular route and the transcellular route. The paracellular transport mechanism implies that drugs diffuse through a space between epithelial cells. On the other hand, an uptake mechanism which depends on lipophilicity involves a typical transcellular transport route, and active transport for amino acids, carrier-mediated transport for (3-lactam antibiotics and dipeptides, and endocytosis are also involved in the transcellular transport system, but these transporters are unlikely to express in rectum (Figure 8.7). Table 8.3 summarizes the typical absorption enhancers in rectal routes. 

Active or carrier-mediated transport involves using membrane proteins to transport substances across the cell membrane (see Fig. 2-2). Membrane proteins that span the entire membrane may serve as some sort of carrier that shuttles substances from one side of the membrane to the other.41 Characteristics of active transport include the following ... 

K0 is now the zero-order rate constant and is expressed in terms of mass/time. In an active carrier-mediated transport process following zero-order kinetics, the rate of drug transport is always equal to K once the system is fully loaded or saturated. At subsaturation levels, the rate is initially first order as the carriers become loaded with the toxicant, but at concentrations normally encountered in pharmacokinetics, the rate becomes constant. Thus, as dose increases, the rate of transport does not increase in proportion to dose as it does with the fractional rate constant seen in first-order process. This is illustrated in the Table 6.1 where it is assumed that the first-order rate constant is 0.1 (10% per minute) and the zero-order rate is 10 mg/min. 

Passive diffusion, carrier-mediated, or active transport across sinusoidal membrane... 

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