Diffusion administered drugs

Orally administered drugs partition into the lipid bilayer in the process of diffusing across the apical and basolateral membranes of the intestinal brush border cells into the blood, as illustrated in Figure 2. About 1800 such drugs are commercially available. A small surface area of the polar parts of the drug molecule generally favors entry into the hydrophobic interior of... 

Coadministration of a P-gp modulator also does not reduce the bioavailability of P-gp substrates when the passive influx of drug greatly exceeds the rate of efflux by P-gp. For instance when therapeutic doses of indinavir are administered intestinal lumen concentrations of this protease inhibitor far exceed its Kin for P-gp-mediated efflux (80 81). Therefore it is likely that indinavir saturates intestinal P-gp at these concentrations and passive diffusion of drug through enterocytes exceeds P-gp-mediated efflux. 

An important aspect of pharmaceutical formulation development is to "facilitate" drug absorption and to ensure that an adequate amount of drug reaches the systemic circulation. Most orally administered drugs enter systemic circulation by way of a passive diffusion process through the small intestine. This is easily seen from the following equation (82) ... 

From an in vitro perspective, solubility in water and in organic solvents determines the choice of solvent, which, in turn, influences the choice of extraction procedure and analytical method. Solubility can also indirecfly impact the timeframe of an assay for compounds that are unstable in solution. From an in vivo perspective, the solubility of a compound influences its absorption, distribution, metabolism, and excretion. Both water solubility and lipid solubility are necessary for the absorption of orally administered antimicrobial drugs from the gastrointestinal tract. This is an important consideration when selecting a pharmaceutical salt during formulation development. Lipid solubility is necessary for passive diffusion of drugs in the distributive phase, whereas water solubility is critical for the excretion of antimicrobial drugs and/or their metabolites by the kidneys. 

Pick s ffrst law law that governs the rate of diffusion across a membrane first-order process a process whose rate is directly proportional to the current amount of the compound being transferred by the process linear elimination pharmacokinetic is an example of a first-order process first pass effect the situation whereby the fraction of a dose of orally administered drug that reaches the systemic circulation is equal to 1 minus its hepatic extraction ratio formulation a dosage form of a particular drug... 

Intramuscularly administered products typically form a depot in the muscle mass from which the drug is slowly absorbed. The peak drug concentration is usually seen within 1-2 hours. Factors affecting the drug-release rate from an IM depot include the compactness of the depot (the less compact and more diffuse, the faster the release), the rheology of the product, concentration and particle size of drug in the vehicle, nature of the solvent or vehicle, volume of the injection, tonicity of the product, and physical form of the product. 

Computational models for blood-brain-barrier penetration have been well reviewed in detail by Clark [36]. Penetration of the blood-brain-barrier (BBB) via passive diffusion is dependent upon the hydrophilicity and lipophilicity of a molecule. However, the BBB is a thicker, more lipophilic membrane than the intestinal membrane. Kelder et al. [37] showed that very few of 776 orally administered CNS drugs had PSA >90, while a substantial fraction of 1590 orally administered non-CNS had PSA >90. These results demonstrate the poor BBB penetration by hydrophilic molecules. 

For example, obesity affects Vi because lipid-soluble drugs diffuse into the adipose tissues of the obese person. Vi is a useful parameter for determining the loading dose for a drug to attain equilibrium after the drug is administered. 

The therapy of a chronic disease requires repeated drug dosing. In the case of a short biological half-life, the drug has to be administered up to several times daily within short intervals. To reduce the application frequency, sustained formulations have been developed. For this purpose liquid crystalline excipients are appropriate candidates, because in a liquid crystalline vehicle the drug diffusion is reduced by a factor of 10 to 1000 in comparison with a liquid vehicle such as a solution [35-37]. The factor depends on liquid crystal. 

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