Diffusion of drugs

United States Patent 4,767,628 assigned to Imperial Chemical Industries describes a similar lactide/glycolide delivery system for LHRH polypeptide (122,123). A multiphase release pattern is again postulated. The first phase occurs by diffusion of drug through aqueous polypeptide domains linked to the exterior surface of the matrix. 

Two principal routes of passive diffusion are recognized transcellular (la —> lb —> lc in Fig. 2.7) and paracellular (2a > 2b > 2c). Lateral exchange of phospholipid components of the inner leaflet of the epithelial bilayer seems possible, mixing simple lipids between the apical and basolateral side. However, whether the membrane lipids in the outer leaflet can diffuse across the tight junction is a point of controversy, and there may be some evidence in favor of it (for some lipids) [63]. In this book, a third passive mechanism, based on lateral diffusion of drug molecules in the outer leaflet of the bilayer (3a > 3b > 3c), wih be hypothesized as a possible mode of transport for polar or charged amphiphilic molecules. 

Artursson, R, Epithelial transport of drugs in cell culture. I A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells, J. Pharm. Sci. 79, 476-482 (1990). 

The time available for metabolism to occur during diffusion of drug across the length of the cells is approximated by the mean residence time (t) ... 

The extent of hydration or solvation of a molecule also has a profound effect on the transport of the substance. The apparent solubility of the drug in both aqueous and nonaqueous media may be influenced by the absence or presence of moisture. Diffusion of drugs in polymeric systems may also be influenced by the hydration of the polymers and hydration of the membrane through which transport is occurring for example, skin hydration may enhance the diffusion of drug molecules significantly. 

To summarize, the hydration status of the drug molecule and other components of a pharmaceutical formulation can affect mass transport. Solubility of drug crystals in an aqueous or nonaqueous solvent may depend on the presence or absence of moisture associated with the drug. Hydration may also determine the hydrodynamic radii of molecules. This may affect the frictional resistance and therefore the diffusion coefficient of the drug molecules. Diffusion of drugs in polymeric systems may also be influenced by the percent hydration of the polymers. This is especially tme for hydrogel polymers. Finally, hydration of... 

Of the following characteristics, which is unlikely to be associated with the process of facilitated diffusion of drugs ... 

Larhed AW, Artursson P, Grasjo J, Bjork E. Diffusion of drugs in native and purified gastrointestinal mucus. J Pharm Sci 1997 86(6) 660-665. 

Lee AJ, King JR, Rogers TG (1996) A multiple-pathway model for the diffusion of drugs in skin. IMA J Math Appl Med Biol 13 127-150. 

Lipid solubility determines the readiness of drug molecules to cross the gastrointestinal tract, blood-brain barrier, and other tissues. Molecular size is another factor that determines the diffusion of drugs across the membrane, with the smaller molecules able to diffuse more readily. Exhibit 5.2 describes the kinetics for diffusion of drug molecules across the cell membrane. 

Presently, clinically useful anticancer compounds are low molecular weight chemicals which possess a high pharamacokinetic volume of distribution, which suggests the ubiquitous presence of toxic compounds in the host. It is this total diffusion of drug throughout the body which results in the majority of toxic effects produced by chemotherapeutic regimens. 

Drug Distribution. After administration, a drug may be distributed either generally or selectively in the body. The distribution pattern depends on many factors, including the pattern and time-course of blood (low, diffusion of drugs into tissues, binding of drugs to plasma proteins and cellular compartments, and elimination kinetics and mechanisms. 

In an evaluation of the diffusion of drugs across the gastrointestinal mucus, the most important physicochemical characteristic influencing the diffusion of most species was lipo-philicity, whereas molecular size had more influence for larger peptide drugs [10]. Binding of... 

Cryotherapy Cold/ice packs Ice massage Cold bath Vapocoolant sprays Decreased pain, edema, and inflammation Muscle relaxation and decreased spasticity Anti-inflammatory steroids (glucocorticoids) nonsteroidal anti-inflammatory analgesics (aspirin and similar NSAIDs) Skeletal muscle relaxants Peripheral vasodilators may exacerbate acute local edema Nonselective cholinergic agonists may stimulate the neuromuscular junction Some forms of cryotherapy may produce local vasoconstriction that temporarily impedes diffusion of drugs to the site of inflammation... 

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) ... 

---