Passive diffusion kinetics

From a thermodynamic and kinetic perspective, there are only three types of membrane transport processes passive diffusion, faeilitated diffusion, and active transport. To be thoroughly appreciated, membrane transport phenomena must be considered in terms of thermodynamics. Some of the important kinetic considerations also will be discussed. 

Figure 41-11. A comparison of the kinetics of carrier-mediated (facilitated) diffusion with passive diffusion. The rate of movement in the latter is directly proportionate to solute concentration, whereas the process is saturable when carriers are involved. The concentration at half-maximal velocity is equal to the binding constant (KJ of the carrier for the solute. maximal rate.)...

During the characterization process, hits are typically tested for kinetic solubility and permeability in a model of passive diffusion such as PAMPA [22]. As new compounds are synthesized, additional parameters also need to be considered, such as pZa, chemical and plasma stability, and protein binding. Calculated properties such as MW, clogP, and PSA should also be tracked. 

Most drugs appear to be absorbed in humans by passive diffusion (linear or first-order kinetics). The predominant pathway taken by most drugs is through the epithelial cell, the transcellular route. It is this route that requires the compound to have a reasonable K0/w... 

The summary of Pe values for the steroids as a function of stirring rates is found in Table 11 and their correlations with log PC (n-octanol-water) in Figure 20. The transport kinetics of the relatively hydrophilic hydrocortisone and dexa-methasone are controlled by passive diffusion across the cell monolayer. On the other hand, the Pe values of testosterone and progesterone are highly dependent on stirring rate. The results for testosterone are used to obtain the relationships between the effective permeability coefficients of the ABL on the donor and receiver sides and the stirring rate, using the linear expression (see Eq. (69)]... 

Raub TJ, CL Barsuhn, LR Williams, DE Decker, GA Sawada, NFH Ho. (1993). Use of a biophysical-kinetic model to understand the roles of protein binding and membrane partitioning on passive diffusion of highly lipophilic molecules across cellular barriers. J Drug Targeting 1 269-286. 

Characteristically, within certain concentration limits, if a chemical is absorbed by passive diffusion, then the concentration of toxicant in the gut and the rate of absorption are linearly related. However, if absorption is mediated by active transport, the relationship between concentration and rate of absorption conforms to Michaelis-Menten kinetics and a Lineweaver-Burk plot (i.e., reciprocal of rate of absorption plotted against reciprocal of concentration), which graphs as a straight line. 

The transport mechanisms that operate in distribution and elimination processes of drugs, drug-carrier conjugates and pro-drugs include convective transport (for example, by blood flow), passive diffusion, facilitated diffusion and active transport by carrier proteins, and, in the case of macromolecules, endocytosis. The kinetics of the particular transport processes depend on the mechanism involved. For example, convective transport is governed by fluid flow and passive diffusion is governed by the concentration gradient, whereas facilitated diffusion, active transport and endocytosis obey saturable MichaeUs-Menten kinetics. 

Figure 3.3 Comparison of the kinetics of carrier-mediated transport and passive diffusion.

In aqueous solution around pH 7, WR 1065 is doubly protonated (net charge Z = 2). Its uptake by mammalian cells is kinetically of first-order and increases with [H+]-1/2. This has been taken as evidence that the transport through plasma membrane probably occurs by a passive diffusion of the uncharged diamine (Calabro-Jones et al. 1988). 

First-order input (11). First-order kinetic input (II) delivers drug at a rate proportional to the concentration gradient driving the transfer of drug movement. A classic example of a first-order kinetic process is the passive diffusion of drug across a homogeneous barrier. The differential equation describing first-order kinetic behavior is shown in Eq. (1.13) ... 

Absorption of purines and pyrimidines by cestodes occurs by a combination of passive diffusion and mediated transport. In H. diminuta, purine and pyrimidine uptake is very complex and seems to involve at least three carrier systems (Table 6.9), two of which appear to bind several substrate molecules simultaneously (631). Pyrimidine transport was thought to involve allosteric regulation because the relation between initial uptake and substrate concentration was sigmoidal. However, more recent work (890) has indicated that the sigmoidal kinetics of pyrimidine transport in H. diminuta is an isotope effect, obtained only when 2-14C-labelled pyrimidines were used absorption kinetics of methyl-l4C- and 3H-labelled pyrimidines were hyperbolic. Nucleosides (thymidine, uridine, adenosine and guanosine) are absorbed by H. diminuta, H. citelli and H. microstoma via a specific sodium-dependent, mediated system involving at least two carriers (347). Interestingly, the mechanism displays a diurnal periodicity in H. diminuta (616, 617). 

Figure 1.5 Kinetics of (A) passive diffusion and (B) active transport...

First-order kinetics is most commonly encountered in ocular drug movement. Here, the rate of movement is directly proportional to the concentration difference across the barrier, and the rate changes with time as the concentration differential across the barrier changes.The passive diffusion of molecules across a nonsaturated barrier generally adheres to first-order kinetics. 

D. Passive diffusion exhibits saturation kinetics, but facilitated diffusion does not. 

The nucieobase 5-FU has been extensively used in the treatment of a variety of malignancies however, very little is known about nucieobase transport in mammalian cells. Actually, hENT2 can transport nucleobases, but it is not responsible for 5-FU uptake [90]. Some authors have suggested that 5-FU is taken up by passive diffusion [91] nevertheless, kinetic analysis of 5-FU uptake into tumor cells indicates that it is energy dependent [92, 93]. 

Figure 9.5 Kinetics of a carrier-mediated membrane transport processes and passive diffusion. At passive diffusion, the transport...

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