Rate of drug transport

Zeolite-polystyrene disks seem to offer reasonable models for comparison in general, and are mechanically stable and reusable. There seem to be special similarities between zeolite X disks and pigskin dermis and between zeolite Y disks and human dermis. The use of these models is being extended to investigate the use of vehicles in drug transport. These are compounds which increase the rate of drug transport through... 

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. 

The rate of drug transport into or out of the tissue bed (r ) is then given by combining Equations (10.19) and (10.32), which yields... 

The rate of drug distribution transport between the central compartment (containing the systemic circulation) and any tissue compartment is taken to follow first-order or linear kinetics. This means that the rate of drug transport from compartment 1 to any other compartment is proportional to the amount of drug in compartment 1. Similarly, the rate of drug transport... 

These equations contain the usual input-output terms of compartmental mass balances and also a simple first-order renal clearance, which is close to inulin clearance for MTX. The Ri are tissue-to-plasma distribution ratios to account for protein binding. The volumes V, and flows, Q, are known from recorded anatomy and physiology. Other parameters are defined as follows kK, renal clearance kL, saturable rate of drug transport into bile KLy saturation constant for bile transport ko, saturable rate of intestinal absorption Kq, saturation constant for intestinal absorption , nonsaturable rate of intestinal absorption kF, reciprocal of nominal transit time in small intestine. 

In Chapter 7, pharmacokinetic models are used to relate local rates of drug transport to the distribution of the drug throughout an organism. 

A number of studies have been undertaken to establish an experimental model for investigating the influence of various barriers on the rate of drug transport. 

Evaporation of the tear film from the precorneal area can cause changes in the concentration of instilled drug solutions, and therefore can affect the rate of drug transport across the ocular membranes. 

JBM Van Bree, AG De Boer, M Danhof, L Gisel, DD Breimer. Characterization of an in vitro blood-brain barrier Effects of molecular size and lipophilicity on cerebrovascular endothelial transport rates of drugs. J Pharmacol Exp Ther 247 1233-1239, 1988. 

Matsukawa Y, Yamahara H, Yamashita F, Lee VH, Crandall ED, Kim KJ (2000) Rates of protein transport across rat alveolar epithelial cell monolayers. J Drug Target 7(5) 335-342... 

The successful application of in vitro models of intestinal drug absorption depends on the ability of the in vitro model to mimic the relevant characteristics of the in vivo biological barrier. Most compounds are absorbed by passive transcellular diffusion. To undergo tran-scellular transport a molecule must cross the lipid bilayer of the apical and basolateral cell membranes. In recent years, there has been a widespread acceptance of a technique, artificial membrane permeation assay (PAMPA), to estimate intestinal permeability.117118 The principle of the PAMPA is that, diffusion across a lipid layer, mimics transepithelial permeation. Experiments are conducted by applying a drug solution on top of a lipid layer covering a filter that separates top (donor) and bottom (receiver) chambers. The rate of drug appearance in the bottom wells should reflect the diffusion across the lipid layer, and by extrapolation, across the epithelial cell layer. 

Although transfer of drugs across the intestinal wall can occur by facilitated transport, active transport, en-docytosis, and filtration, the predominant process for most drugs is diffusion. Thus, the pK of the drug and the pH of the intestinal fluid (pH 5) will strongly influence the rate of drug absorption. While weak acids like phenobarbital (pK 7.4) can be absorbed from the stomach, they are more readily absorbed from the small intestine because of the latter s extensive surface area. 

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