Cellular membrane permeation

Industrial enzymes may be produced by animal, vegetable, or microbial cells. Only microbial enzymes have been commercially successful because of the genetic fiexibility of microorganisms. Moreover, the exocellular enzymes they secrete are much more easily isolated than endocellular enzymes The isolation of endocellular enzymes requires a preliminary step of cellular membrane permeation and the removal of enzyme from the cell s binding site without damage. Enzymes of bacterial origin are also usually more thermostable. 

While in vivo studies assess absorption rates as process-lumped time constants from blood level versus time data, these rate parameters encompass the kinetics of dosage-form release, GI transit, metabolism, and membrane permeation. The use of isolated tissue and cellular preparations to screen for drug absorption potential and to evaluate absorption rate limits at the tissue and cellular levels has been expanded by the pharmaceutical industry over the past several years. For more detail in this regard, the reader is referred to an article by Stewart et al. [68] for references on these preparations and for additional details on the various experimental techniques outlined below. 

Practically all anaerobic Gram-negative bacteria are resistant to lincosamides. Resistance to lincosamides can occur because of the inability of drugs to permeate through the cellular membrane of bacteria, or because of changes in the ribosomal-binding regions. 

Falten et al. recently reported that phospholipid membrane vesicles can be con-stmcted on a filter scaffold without any organic solvent [57-60]. In this system, the phospholipid vesicle occupies the filter pores to form a permeation barrier. This is more relevant to the cellular membrane than PAMPA membranes with organic solvent. The membrane can be stored up to two weeks without significant change and is stable at pH 2-8. The Fa% predictability was compared with BM-PAMPA, DS-PAMPA, Caco-2 and immobilized liposome chromatography, resulting in promising predictability. 

Godin, B., and E. Touitou. 2004. Mechanism of bacitracin permeation enhancement through the skin and cellular membranes from an ethosomal carrier. J Control Release 94 365. 

The range of applications of peptide drugs is very broad, and includes analgesia, cancer therapy, and infection treatment. The processing and delivery of proteins are often challenging, as many protein molecules are physically and chemically unstable. Once administered, proteins can be subject to enzymatic degradation, and present unfavorable permeation through cellular membranes. 

Figure 15.8 I BD and glucocorticoid resistance. Normally, glucocorticoids permeate through the cellular membrane into the cytoplasm where they bind to glucocorticoid receptors gray arrows). These receptors dimerize and translocate into the nucleus, where they bind to the promoters of their target genes and either activate or inactive transcription. Glucocorticoids inhibit the transcription of AP-1 and of proinflammatory proteins (PI Ps) but activate the transcription of...

Pharmacokinetic characteristics of drug molecules concern the processes of absorption, distribution, metabolism, and excretion. The biodisposition of a drug involves its permeation across cellular membrane barriers. 

The permeation of most drugs through cellular membranes is by the process of passive diffusion, a nonsaturable process that follows first-order kinetics. Concentration gradient and lipid solubility of the drug are important determinants of the rate of diffusion. Only a few drug molecules are substrates for active transport processes (eg, tubular secretion of beta-lactam antibiotics) these are saturable at high concentrations. Only very small ions (eg, Li+) or drugs (eg, ethanol) may penetrate biomembranes via aqueous pores. 

Oxidizing substances, such as ozone, can cause peroxidation of cellular membranes, leading to membrane damage and increased permeability. The edematous fluid permeates through such membranes, accumulating and blocking the airway. This results in edema. Many other toxicants may produce cellular damage and edema, however. 

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