Membranes, cell drug passage across

Time course of drug concentration Drug passage across cell membranes Order of reaction Plasma half-life and steady-state concentration Therapeutic drug monitoring... 

An ability to penetrate lipid bilayers is a prerequisite for the absorption of drugs, their entry into cells or cellular organelles, and passage across the blood-brain barrier. Due to their amphiphilic nature, phospholipids form bilayers possessing a hydrophilic surface and a hydrophobic interior (p. 20). Substances may traverse this membrane in three different ways. 

Drug distribution in such sites or compartments is a complex process that depends on the systemic circulation concentration and subsequent passage across single cell endothelial or epithelial membranes with specialized physical and molecular barrier functionality. For certain orally administered AIDS medications (e.g., zidovudine and didanosine), oral absorption is limited because of poor absorption from the G1 tract, enzymatic biotransformation in the intestinal epithelium, or first-pass effects (Sinko et al., 1995, 1997). For other AIDS drugs (e.g., protease inhibitors), oral absorption may be complete however, drug distribution into the brain is limited by drug efflux proteins, which promiscuously interact and translocate lipophilic substrates back into blood as they diffuse into the BBB endothelium (Edwards et al., 2005 Kim et al., 1998). 

The absorption, distribution, metabolism, and excretion of a drug all involve its passage across cell membranes (Figure 1-1). 

Lipid solubility of the drug is the determining factor for the penetration of cell membranes. Therefore, the passage of many drug molecules across the membranes of the skin, oral cavity, bile, tissue cells, kidneys, central nervous system and the gastrointestinal epithelium is very much related to the lipid solubility of the drug molecule. 

Figure 3.3 The passage of drugs across cell membranes.

In an effort to address the poor membrane permeation of L-767,679, the benzyl ester pro-drug, L-775,318 was synthesized (Fig. 13.2) The latter compound exhibited significant lipophilicity (log P = 0.7) that was consistent with improved potential to cross the enterocyte membrane. However, this did not lead to a marked improvement in absorption potential (in the rat), as intestinal hydrolysis and counter-transport combined to prevent significant passage of the compound across Caco-2 cells and the rat gut. 

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