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Pharmacokinetics- Membrane Transport, Absorption, Distribution, Metabolism and Excretion of Drugs

Membranes do not play an active role in the diffusion of medication through the membrane, which follows the gradient of concentration.
The medication is transported across biological membranes in all pharmacokinetic processes.

Membrane biological

Hydrocarbon chains are embedded in the matrix of the sheet, and polar groups are oriented at the surfaces (glyceryl phosphate is attached to ethanolamine/choline or hydroxyl group is attached to cholesterol). Due to this, the membrane is highly electrically resistive and relatively impermeable. Protein molecules, both extrinsic and intrinsic, are adsorbed on the lipid bilayer.



By attaching to polymeric sugars, amino-sugars, or sialic acids, glycoproteins and glycolipids form on the surface. The lipid and protein makeup of various membranes varies depending on the cell or organelle type. Proteins can easily float over the membrane, allowing them to interact and organize or vice versa. Some of the intrinsic ones, which run the whole width of the membrane, encircle fine aqueous holes.



There are also paracellular gaps or channels between specific epithelial/endothelial cells. Other proteins that have been adsorbed contain enzymatic, carrier, receptor, or signal transduction capabilities. Lipid molecules can travel laterally as well. As a result, biological membranes are extremely dynamic structures.

The following mechanisms allow drugs to pass through membranes:

Passive diffusion

Membranes do not play an active role in the diffusion of medication through the membrane, which follows the gradient of concentration. It is the mechanism by which the body reacts to the majority of medicines; pharmaceuticals are foreign chemicals (xenobiotics), and the body develops specialized mechanisms in response to natural compounds.

A liposoluble drug diffuses through the lipoidal matrix of the membrane at a rate proportional to its water: lipid partitioning coefficient. A medication that is more lipid-soluble achieves a larger concentration in the membrane and diffuses more rapidly. When a drug diffuses slowly, the difference between its concentration on either side of the membrane is greater.

Filtration

Filtration is the process of transporting pharmaceuticals through aqueous pores in membranes or through gaps in paracellular membranes. Most capillaries, including glomeruli, contain hydrodynamic pressure gradients that permit the solvent to flow hydrodynamically. If the molecular size of the medicine is less than the diameter of the pores, it can pass through biological membranes via filtration. The majority of cells (intestinal mucosa, RBC, etc.) have relatively tiny holes (4), and medicines with MW greater than 100 or 200 cannot permeate. However, capillaries (save those in the brain) have extensive paracellular gaps (40), through which most medications (including albumin) may pass. As a result, drug diffusion across capillaries is determined by the velocity of blood flow through them rather than the drug's lipid solubility or the medium's pH.

Specialized transport

This can be caused by a carrier or by pinocytosis.

Transport by carrier




Facilitated diffusion occurs when the carrier (SLC) attaches to and transports the weakly diffusible substrate down its concentration gradient (from high to low) without the need of energy.

The carrier (ABC) receives energy immediately from hydrolyzing ATP and transports the substrate against its concentration gradient in primary active transport (low to high).

Using the energy from another substrate 'B' moving in the same direction as the substrate 'A,' the carrier propels that substrate 'A' against its concentration gradient.

Carriers transport substrates 'A' against their concentration gradients and are powered by another substrate's downhill motion via channels in the opposite direction to the flux. Depending on energy requirements, carriers can either:

Unlike traditional transporters, diffusion-facilitated transporters act passively and without using energy to move substrates along an electrochemical gradient, i.e., from higher to lower concentrations. The improvement is limited to substrates that are weakly diffusible, such as glucose transporter GLUT 4 entering muscle and fat cells.

It is an active transport system, requiring energy and blocked by metabolic toxins. This transport method transports solutes against their electrochemical gradient (from low to high), causing the material to accumulate selectively on one side of the membrane. Drugs that are similar to natural metabolites can use the transport systems designed for them; for example, the aromatic amino acid transporter actively absorbs levodopa and methyl dopa from the stomach. Furthermore, to deal with xenobiotics, the body has produced several rather nonselective transporters, such as P-glycoprotein (P-gp). Active transportation might be the primary or secondary mode of transportation, depending on its source.

In active primary transportation, the hydrolysis of ATP produces energy immediately. The transporters are members of the ATP binding cassettee (ABC) transporter superfamily, and their intracellular loops contain ATPase activity. They are primarily responsible for enabling solute efflux from the cytoplasm to extracellular fluid or intracellular organelles (endoplasmic reticulum, mitochondria, etc.).

One type of active transport involves the second set of SLC transporters in which the energy for pumping one solute originates from the descent of another (mostly Na+). When concentration gradients induce both solutes to flow in the same direction, this is called symport or cotransport; when they move in opposite directions, this is called antiport or exchange transport. Metabolic energy (derived from ATP hydrolysis) is expended in maintaining a large transmembrane electrochemical gradient of the second solute (often Na+). SLC transporters mediate drug and metabolite absorption and efflux.

Carrier transfer follows Michaelis-Menten kinetics (both assisted diffusion and active transport) and is saturable. The transport rate is calculated by determining the density of the transporter in the membrane based on its affinity for the substrate (Km). At half maximum substrate concentration, the transport rate is half-maximal based on its affinity for the substrate. By genetically modifying transporter proteins, one can affect their affinities for various substrates, which has a bearing on pharmacokinetics. Furthermore, due to the presence of specialized transporters in certain cells, tissue-specific drug distribution might occur.

Pinocytes

Vesicles transport particles across the cell by forming a vesicle network. This is true for proteins and other large molecules, but it makes little difference in the transport of most medications, with the exception of vitamin B12, which is absorbed from the stomach after binding to an intrinsic factor (a protein).

The transport of medication from its place of delivery into circulation is referred to as absorption. A critical aspect of determining how effective a medication is to examine not only the fraction absorbed but also the rate of absorption. Except when administered intravenously, the medication must pass biological membranes; absorption is regulated by the principles stated above. Other elements that influence absorption include:

Solubility in water Before drugs in solid form can be absorbed, they must dissolve in the aqueous BioPhase. For medications that are weakly water-soluble (aspirin, griseofulvin), the rate of dissolution affects the rate of absorption. Ketoconazole dissolves at low pH and requires stomach acid to be absorbed. A medicine supplied as a watery solution is obviously absorbed faster than the same drug delivered in solid form or as an oily solution. Concentration gradients influence passive diffusion; a medicine given in a concentrated solution is absorbed faster than a drug given in a dilute solution.

Absorption surface area the larger the surface area, the faster the absorption.

The absorbing surface's vascularity the medication is removed from the site of absorption by blood circulation, which maintains the concentration gradient throughout the absorbing surface. Increased blood flow speeds up drug absorption, much as wind speeds up clothing drying.

Because each route has its own eccentricities, the route of administration has an effect on pharmaceutical absorption.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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