Transport passive

As for active drug transport, there is no quantitative relationship between passive drug permeability in Caco-2 cells in vitro and drug transport in the human small 

In gas permeation, a gas species is separated based mainly on its permeability in hollow fiber and spiral wound membranes. The hollow fiber systems can have an inside diameter up to 200 xm and hence very large surface-to-volume ratios, but high pressure drops inside the tubes. The basic flow equation for a species / is 

The selectivity should be greater than 20 to accomplish significant separation of species / from species j. For a completely mixed membrane system, the external mass balance yields 

This equation reduces to the following quadratic form once the fractions are eliminated  

the apparent membrane permeability characteristics of hydrophilic compounds listed in Table 3.4 indicate that colonic epithelium is different from small intestinal epithelium in selectivity, or size or density distribution of the paracellular pathway. This is further complicated because of the possible involvement of unidentified carriers or channels for some compounds, as suggested for glycerol and D-xylose. However, the colon-to-SI ratios of the apparent membrane permeability are generally comparable with (or lower than) those calculated considering the morphological surface area, suggesting that such factors are not in favor for colonic absorption in most cases. Matching 

Compound MW logPo/w (mM) Colon SI Colon SI Colon/SI Reference 

Note Data represent the mean S.E. (n = 3). MW, molecular weight P0/w, octanol-to-water partition coefficient CLapp, apparent membrane permeability clearance SI, midgut area of the small intestine NA, not available or applicable. Absorption was evaluated in our laboratory using the closed loop of the rat intestine in situ (urethane anesthesia, 1.125 g/4.5 ml/kg, i.p.) in 60 min for riboflavin and L-camitine and 30 min for the others. For those that are transported by carriers in part (riboflavin and glycerol in both colon and SI, and L-carnitine, 5-fluorouracil, and cephradine in SI), absorption was evaluated at higher concentrations where the contribution of carrier-mediated transport is negligible. Values of P0/w were obtained from a report by Leo et al. [30] except for that of D-xylose, which was determined in our laboratory. a Data by single-pass perfusion experiments. b Unpublished data from our laboratory. 

Chapter 3 Drug Absorption from the Colon In Situ 85 

Reduced AA exists predominantly as the ascorbate anion in most body fluids. Molecules that are comparably water soluble diffuse rapidly through nonspecific pathways in cell membranes, especially through the lipid bilayer. In contrast, ascorbate, because of its size and charge, does not readily permeate the lipid bilayer. Simple diffusion of DHAA into cells is negligible probably due to the structure and water nucleation around the molecule. Weak organic acids can enter cells by simple diffusion of their undissociated forms. Once in the cytoplasm, these acids dissociate into organic ions and protons. However, it has been demonstrated that this process did not occur for AA (Wilson and Dixon, 1989). 

When ascorbate acts as an antioxidant or enzyme cofactor, it becomes oxidized to DHAA. Ascorbate and DHAA possess roughly equivalent bioavailability. Bioavailability is determined by the rates of absorption, distribution, and metabolism within the body, and by excretion. Ascorbate and DHAA are absorbed along the entire length of the human intestine (Malo and Wilson, 2000). For both the DHAA and ascorbate transport systems, initial rates of uptake saturate with increasing external substrate concentration, reflecting high-affinity interactions that can be described by Michaelis-Menten kinetics. 

The mechanism of DHAA uptake by luminal membranes of human jejunum has pharmacological characteristics that clearly differ from those of ascorbate uptake. Sodium-independent carriers take up DHAA by facilitated diffusion, and these are distinct from the sodium-dependent transporters of ascorbate. Glucose inhibits ascorbate uptake but not DHAA uptake, which raises the possibility that glucose derived from food may increase the bioavailability of DHAA relative to ascorbate (Malo and Wilson, 2000). Human enterocytes contain reductases that convert DHAA to ascorbate (Buffinton and Doe, 1995). This conversion keeps the intracellular level of DHAA low, and the resulting concentration gradient favors uptake of oxidized AA across the enterocyte plasma membrane. 

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Fig. 2. Schematic representation of relevant electrolyte transport through the renal tubule, depicting the osmolar gradient ia medullary iaterstitial fluid ia ywOj yW where represents active transport, —passive transport, hoth active and passive transport, and passive transport of H2O ia the presence of ADH, ia A, the cortex, and B, the medulla. An osmole equals a mole of solute divided by the number of ions formed per molecule of the solute. Thus one mole of sodium chloride is equivalent to two osmoles, ie, lAfNaCl = 2 Osm NaCl. ADH = antidiuretic hormone.

Proteins that can flip phospholipids from one side of a bilayer to the other have also been identified in several tissues (Figure 9.11). Called flippases, these proteins reduce the half-time for phospholipid movement across a membrane from 10 days or more to a few minutes or less. Some of these systems may operate passively, with no required input of energy, but passive transport alone cannot establish or maintain asymmetric transverse lipid distributions. However, rapid phospholipid movement from one monolayer to the other occurs in an ATP-dependent manner in erythrocytes. Energy-dependent lipid flippase activity may be responsible for the creation and maintenance of transverse lipid asymmetries. 

In other words, the negative charge is spontaneously attracted to the more positive potential—and AG is negative. In any case, if the sum of the two terms on the right side of Equation 10.2 is a negative number, transport of the ion in question from side 1 to side 2 would occur spontaneously. The driving force for passive transport is the AG term for the transported species itself. 

On the other hand, Bartsch et al. have studied cation transports using crown ether carboxylic acids, which are ascertained to be effective and selective extractants for alkali metal and alkaline earth metal cations 33-42>. In a proton-driven passive transport system (HC1) using a chloroform liquid membrane, ionophore 31 selectively transports Li+, whereas 32-36 and 37 are effective for selective transport of Na+ and K+, respectively, corresponding to the compatible sizes of the ring cavity and the cation. By increasing the lipophilicity from 33 to 36, the transport rate is gradually... 

This review surveys the types of host molecules that are applicable to the active transport system. It need scarcely be said that these results, which are based on selective transport in passive transport systems (see the Chaps. 3 and 5), strongly supports this consideration. From this point of view, a systematic investigation into the passive transport system as that by Izatt et al. is noted as one of the best approaches for clarifying the question of membrane transport77). 

Invasive pathogens either aggressively invade the tissues surrounding the primary site of infeehon or are passively transported around the body in the blood, lymph, cerebrospinal fluid or pleural fluids. Some, espeeially aggressive organisms, do both, setting up a number of expansive seeondary sites of infeehon in various organs. 

Thus the picture that emerges at this point is that in the membrane probably a diprotomeric (a) )2 structure (oc is 114 kDa, P is 60-80 kDa) is responsible for the active transport process. On the other hand the minimal structure for K -ATPase activity, K -pNPPase activity, passive transport and phosphorylation is either an otp protomer or another larger oligomeric structure. 

ATPase also catalyzed a passive Rb -Rb exchange, the rate of which was comparable to the rate of active Rb efflux. This suggested that the K-transporting step of H,K-ATPase is not severely limited by a K -occluded enzyme form, as was observed for Na,K-ATPase. Skrabanja et al. [164] also described the reconstitution of choleate solubilized H,K-ATPase into phosphatidylcholine-cholesterol liposomes. With the use of a pH electrode to measure the rate of H transport they observed not only an active transport, which is dependent on intravesicular K, but also a passive H exchange. This passive transport process, which exhibited a maximal rate of 5% of the active transport process, could be inhibited by vanadate and the specific inhibitor omeprazole, giving evidence that it is a function of gastric H,K-ATPase. The same authors demonstrated, by separation of non-incorporated H,K-ATPase from reconstituted H,K-ATPase on a sucrose gradient, that H,K-ATPase transports two protons and two ions per hydrolyzed ATP [112]. 

Mechanisms of active and passive transport in a family of homologous sugar transporters found in both prokaryotes and eukaryotes... 

It is clearly impossible to give a comprehensive overview of this rapidly expanding field. I have chosen a few experts in their field to discuss one (class of) transport protein(s) in detail. In the first five chapters pumps involved in primary active transport are discussed. These proteins use direct chemical energy, mostly ATP, to drive transport. The next three chapters describe carriers which either transport metabolites passively or by secondary active transport. In the last three chapters channels are described which allow selective passive transport of particular ions. The progress in the latter field would be unthinkable without the development of the patch clamp technique. The combination of this technique with molecular biological approaches has yielded very detailed information of the structure-function relationship of these channels. 

In the attempt to overcome the contradictions, the assumption must be made that aside from passive transport in the cell, an active transport of Na ions from the cytoplasm to the external solution is accomplished by the action of peculiar molecular pumps. 

Ordinarily, when the current pulse is over, the excess charges will be drained through the passive transport channels, and by operation of the sodium-potassium pumps the original values of membrane potential and of the concentration gradients will be reestablished. However, when in the case of depolarization the negative value of cp has dropped below a certain threshold value, which is about -50 mV, the picture changes drastically Excitation of the membrane occurs. When the current is turned off, the membrane potential not only fails to be restored but continues to... 

E. P., McEarland,. W., Schaper, K.-J. Quantitative estimation of drug absorption in humans for passively transported compounds on the basis of their physico-chemical parameters. 

Kelder et al. [25] collected a set of 776 orally administered CNS drugs that are known to be passively transported into the brain and have entered at least phase... 

Clark, D. E., Grootenhuis, D. J. Predicting passive transport in silica - history, hype, hope. Curr. Top. Med. Chem. 2003, 3, 1193-1203. 

For 31 passively transported dmgs, excellent sigmoidal relationships were found between human intestinal absorption and their H-bond acceptor and donor factors [65] ... 

A volume-related term (expressed by polarizability) and electrostatics (expressed by partial atomic charge) made minor contributions to intestinal absorption in humans. Lipophilicity, expressed by logP or logD values, shows no correlation with the human absorphon data. Recently, similar results were obtained for 154 passively transported drugs on the basis of surface thermodynamics descriptors [39] ... 

Except the special case of large particles and proteins that enter the cell by endocy-tosis [19], the transport of molecules across biomembranes can be divided into two categories [20] active and passive transport. 

FIG. 1 Differentiation between active and passive transport. (Adapted from Ref. 46.)... 

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