Pharmacology
Summary
Lipophilic compounds, also known as hydrophobic (water-fearing) substances, are non-polar in nature and thus soluble in nonpolar lipids. Conversely, hydrophilic (or lipophobic) drugs are polar and soluble in water. The partition coefficient (P) measures a drug's affinity for a lipid or aqueous environment. A drug with a P value > 1 is hydrophobic, while a P value < 1 indicates a hydrophilic drug. The structural makeup of cell membranes consists of a phospholipid bilayer, with the hydrophobic parts pointing inward and the hydrophilic parts facing the surrounding aqueous environment. To reach their target tissue, drugs need to permeate several of these membranes, any of which could pose as the rate-limiting step. Drug molecules traverse these membranes predominantly via passive transcellular movement, moving directly through the cell membrane. However, some particularly polar or lipophobic drugs utilize the paracellular movement, passing through the aqueous spaces between cells. In other scenarios, drugs may utilize facilitated transcellular pathways, accessing transport systems like protein channels. This could be a passive process--moving down a concentration gradient--or an active one, going against the gradient.
Passive diffusion is a vital process in drug permeation, where molecules move from areas of high concentration to those of low concentration. Several factors influence the ease of this passage: increased molecular weight or thickness decreases it, while heightened lipophilicity, larger gaps between cells, and fenestrations increase it. Passive diffusion continues until equilibrium is attained, at which point the rate of flux across the membrane is balanced in both directions, leading to a net movement of zero. There are also carrier-mediated transport systems that might reach their maximum capacity, causing a phenomenon known as capacity-limited transport. Active transport systems employ ATP to actively move drugs against a concentration gradient. One key example of this is the P-glycoprotein (Pgp) efflux pump, which actively exports drugs and toxins from cells for excretion, utilizing 2 ATP molecules in the process.
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FAQs
The partition coefficient (P) is a measure that indicates the preference of a drug to distribute itself between two immiscible phases, commonly a lipophilic (non-polar) and a hydrophilic (polar) phase. It is calculated as the concentration of unionized drug in the n-octanol or organic phase divided by the unionized concentration in the water or aqueous phase. Hydrophobic (lipophilic) drugs exhibit a P value greater than 1, implying a greater distribution in lipophilic phases, whereas hydrophilic drugs showcase a P value less than 1, indicating a higher solubility in water or aqueous phases.
Passive diffusion and active transport are two processes by which drugs permeate through cell membranes. In passive diffusion, drug molecules move from an area of high concentration to an area of low concentration, following the concentration gradient. Factors such as the drug's molecular weight, lipophilicity, charge/ionization, and the membrane's thickness affect the ease of passage via passive diffusion. In contrast, active transport uses ATP to move drugs against the concentration gradient, i.e., from low to high concentration. It is often utilized when the concentration of substances inside a cell must be maintained differently from their concentration in the extracellular fluid. One example is P-glycoprotein (Pgp), an efflux pump that transports drugs and toxins out of the cell to be excreted, thereby using 2 ATP molecules in the process.
Facilitated transcellular pathways are mechanisms where a drug molecule uses transport systems or proteins channels to enter a cell. These pathways can be passive, which means the drug moves down the concentration gradient, or active, wherein the drug moves against the concentration gradient. This method is particularly useful when a drug molecule is unable to cross the lipid bilayer due to its chemical properties, such as being highly charged.
Cell membranes are arranged into a phospholipid bilayer where the hydrophobic (lipophilic) parts point into the center of the membrane and the hydrophilic (polar) parts are oriented towards the aqueous environment. As such, drugs must pass through multiple membranes to reach the target tissue. The drug's passage can be affected by its characteristics like being hydrophilic or hydrophobic and its ability to pass through these lipid layers. The rate at which it crosses these membranes can often be the rate-limiting step in drug absorption and distribution.
Paracellular movement refers to when a drug molecule passes through the aqueous spaces between cells rather than directly crossing the cell membrane. This type of movement is generally associated with drugs that are particularly polar or lipophobic, meaning they have difficulty moving across the lipid-rich environment of the cell membrane. As a result, these drugs rely on the spaces between cells for transport – hence, the term 'paracellular'. It is important to note that the size of these gaps and fenestrations can influence the ease of passage via paracellular movement.
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