Drug distribution active transport

Unchanged passive diffusion and no change in bioavailability for most drugs l Active transport and i bioavailability for some drugs l First-pass extraction and T bioavailability for some drugs i Volume of distribution and T plasma concentration of water-soluble drugs T Volume of distribution and T terminal disposition half-life (t ) for fat-soluble drugs... 

Lipinski et al. at Pfizer [11] analyzed the distribution of physicochemical properties of 2245 drugs from the WDI that have entered clinical trials after excluding natural products and actively transported molecules. They proposed the Rule-of-5 to indicate that poor absorption or permeation is more likely when ... 

Kelder et al. [19] have shown that PSA can be used to model oral absorption and brain penetration of drugs that are transported by the transcellular route. A good correlation was found between brain penetration and PSA (n=45, r=0.917). From analyzing a set of 2366 central nervous system (CNS) and non-CNS oral drugs that have reached at least phase 11 clinical trials it was concluded that orally active drugs that are transported passively by the transcellular route should have PSA< 120 Al In addition, different PSA distributions were found for CNS and non-CNS drugs. 

FIG. 2 Mechanisms of drug transfer in the cellular layers that line different compartments in the body. These mechanisms regulate drug absorption, distribution, and elimination. The figure illustrates these mechanisms in the intestinal wall. (1) Passive transcellular diffusion across the lipid bilayers, (2) paracellular passive diffusion, (3) efflux by P-glycoprotein, (4) metabolism during drug absorption, (5) active transport, and (6) transcytosis [251]. 

Lipophilicity is an important property of molecules in relation to their biological activities. It is one of the key physiochemical parameters that determine the distribution and transport of drugs into the body and target organs. Measurements of lipophilicity, expressed as the logarithm of the... 

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. 

After a drug is absorbed, it is distributed into various tissue compartments. The rate at which this occurs is determined by the blood flow to the tissues as well as the rate of transfer of the drug from the blood into the tissues. This transfer depends on the vascular permeability to the drug, the relative binding of the drug to blood versus tissue components, the availability of active transport processes, and the concentration gradient... 

Factors analogous to those affecting gut absorption also can affect drug distribution and excretion. Any transporters or metabolizing enzymes can be taxed to capacity—which clearly would make the kinetic process nonlinear (see Linear versus Nonlinear Pharmacokinetics ). In order to have linear pharmacokinetics, all components (distribution, metabolism, filtration, active secretion, and active reabsorption) must be reasonably approximated by first-order kinetics for the valid design of controlled release delivery systems. 

The volume of distribution of a peptide or protein drug is determined largely by its physico-chemical properties (e. g., charge, lipophilicity), protein binding, and dependency on active transport processes. Due to their large size - and therefore limited mobility through biomembranes - most therapeutic proteins have small volumes of distribution, typically limited to the volumes of the extracellular space [26, 51]. 

Chirality does not really become a significant factor unless enantioselectivity exists in processes such as active transport. The distribution of a drug can be markedly affected by its ability to bind to plasma proteins since only a free drug is able to cross... 

If we make the assumptions that drug distribution to and from the site of action is first order (i.e./ no active transport is involved) and that drug actions are directly determined by the unbound/ unionized drug concentration in water at the site of actioii/ then at steady state the drug concentration in plasma water will be directly proportional to its concentration at the site of action. We can therefore use parameters estimated from biophase concentrations (such as the EC50) to predict the drug effects from unbound/ unionized plasma concentrations. 

Volume of Distribution Volume of distribution is the space in which the drug appears to distribute. Volume of distribution is a complex relationship between water and lipid solubility, drug binding to plasma and tissue proteins, and active transport systems. 

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