Lipids ionization and

Al-Saad, K. A. Zabrouskov, V. Siems, W. F. Knowles, N. R. Hannan, R. M. Hill, H. H. Matrix assisted laser desorption/ionization time-of-flight mass spectrometry of lipids ionization and prompt fragmentation patterns. Rapid Comm. Mass Spec-trom. 2003,17, 87-96. 

At mucosal pH where drug is 100% ionized and Eq. (4) has accounted for pH partition shifts, nonzero permeability suggests that ionized drug (Kp close to zero) permeates the membrane by a route other than via lipid partition/diffusion. A discussion of such alternative pathways follows in Section m.C. 

The exit of drugs from the CNS can involve (1) diffusion across the blood-brain barrier in the reverse direction at rates determined by the lipid solubility and degree of ionization of the drug, (2) drainage from the cerebrospinal fluid (CSP) into the dural blood sinuses by flowing through the wide channels of the arachnoid villi, and (2) active transport of certain organic anions and cations from the CSF to blood across the choroid plexuses... 

Opioid levels in the brain are significant within seconds to minutes after injection. As mentioned before, heroin is more lipid soluble than morphine, so a greater amount penetrates the brain. Lipid solubility and ionization are the predominant factors that determine the distribution of opioids (Mather 1987). At therapeutic concentrations, about one-third of morphine is bound to protein in the blood. 

Cell membranes are stmctures containing lipids and proteins as their main components. Many dmg molecules are weak acids or bases and can, therefore, exist as ionized species, depending upon their pATa values and the pH of the environment. One of the more important concepts relating to drug absorption is that ionized species have very low lipid solubility, and are unable to permeate through membranes. Only the non-ionized dmg is usually able to cross membranes. A range of pATa values covered by some common dmgs is shown in Table 4.11. 

Injury to cell plasma membrane can activate acid sphingomyelinase to break down membrane lipid sphingomyelin and generate the second messenger ceramide, a complex lipid, to initiate the apoptosis (HI). Ceramide, perhaps through intracellular mitogen-activated protein kinases (MAPK), can alter cellular susceptibility to TNF-a, FasL, and ionizing radiation-induced apoptosis (HI, Wll). 

Upon irradiation of fats, the formation of a multitude of products is possible after primary ionization and excitation, and deprotonation followed by various dimerization, disproportionation reactions, dissociations, or decarboxylation. It is generally assumed that irradiation in the presence of oxygen leads to accelerated autooxidation of lipids, and that the pathways are the same as in light-induced or metal-catalyzed autooxidation. 

Apart from the properties of the cell membranes, certain physicochemical characteristics of the drugs can significantly influence the rate of their absorption. Most drugs are either weak acids or bases that exist in solution as a mixture of ionized and nonionized forms. Nonionized forms are more lipophilic whereas ionized forms more hydrophilic. Consequently, the nonionized forma are lipid soluble and able to permeate rapidly across cell membranes. This process is known as passive nonionic diffusion. 

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