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PHARMACOKINETICS: THE DYNAMICS OF DRUG ADME Passage of Drugs Across Membrane Barriers: The Plasma Membrane Is Selectively Permeable- - The plasma membrane consists of a bilayer of amphipathic lipids with their HC chains eriented inward to the center of the bilayer to form a continuous hydrephebic phase, with their hydrophilic heads oriented outward. ~ Individual lipid molecules in the bilayer vary ace: the particular membrane and can move laterally and organize themselves into microdomains (e.g, regions with sphingelipids and cholesterol, forming lipid rafts), endewing the membrane with fluidity, flexibility, organization, high electrical resistance, and relative impermeability to highly polar molecules. - Membrane proteins embedded in the bilayer serve as structural anchors, receptors, ion channels, or transporters to transduce electrical or chemical signaling pathways and provide selective targets for drug actions. - Far from being a sea of lipids with proteins floating randomly about, membranes are ordered and compartmented with structural scaffolding elements linking to the cell interior. Modes of Permeation and Transport: Passive Diffusion:— - In passive transport, the drug molecule usually penetrates by diffusion aleng a conc gradient by virtue of its solubility in the lipid bilayer. - Such transfer is directly proportional to the magnitude of the concentration gradient across the membrane, te the lipid-water partition coefficient of the drug, and to the membrane surface area exposed to the drug, - At steady state, the cone of the unbeund drug is the same on both sides of the membrane if the drug is a nen electrolyte. ~ Fer ionic compounds, the steady-state conc depend on the electrochemical gradient for the ion and on differences in pH across the membrane, which will influence the state of ionization of the molecule disparately on either side of the membrane and can effectively trap ionized drug en one side of the membrane.