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What are the Different modes of biotransportation of drugs - how drugs move across the cell membrane? - ePharmacology
Biotransport is defined as the translocation of a solute from one side of the biological barrier to the other, the transferred solute appearing in the same form on both side of the biological barrier. In most cases the translocation of solutes occurs through cells and not between them. That is, it must pass through plasma membrane rather than intercellular space.
A little about the Plasma membrane of cells
The outer thin (about 7.5 nm) covering of the animal cell is the plasma membrane.
It has been possible to understand the structural and functional properties of the plasma membrane using:
- X-ray diffraction
- Electron microscope
- Nuclear magnetic resonance technique
- Special histochemical staining techniques
- Immunological reactions
- Chemical analysis
Transmission electron microscope shows that the plasma membrane has a butter sandwich organization, consisting of two densely staining parallel sheets separated by a faintly staining inner core.
Plasma membrane is composed of lipid and protein molecules.
The major classes of membrane lipids are phospholipids and cholesterol which form the main framework.
One part of the phospholipid and the cholesterol molecule is soluble in water through its tendency toward hydrogen bond forming, that is hydrophilic (the Greek word hydro, for water, and philos, meaning a tendency toward), whereas the other part is insoluble in water but soluble in organic solvent, that is hydrophobic (the Greek word hydro, for water, and phobos, meaning to fear).
The hydrophilic end glyceryl phosphate attached to an amine or the cyclic polyhydric alcohol in the case of the phospholipids or the terminal hydroxyl group of cholesterol orient themselves at both the inner and outer surfaces, while the hydrophobic portions- hydrocarbon chains of the phospholipids or the main bulk of cholesterol molecules occupy the center of the membrane.
The phospholipid molecules are arranged in two parallel rows (a double layer of lipid molecules).
X-ray diffraction is a powerful tool to study the three-dimensional structure of proteins.
Here, a narrow beam of X-rays is fired at the crystals of a protein. Crystals are usually formed by adding the macromolecule to a concentrated salt solution.
Part of the beam goes straight through the crystal. The rest is scattered (diffracted) in various directions.
The diffracted beams are detected by X-ray film, the degree of blackening of the emulsion is proportional to the intensity of the diffracted X-ray beam.
The degree of scattering of the X- rays is determined by the number of electrons in an atom. For example, a carbon atom scatters six times as strongly as a hydrogen atom.
The protein molecules appear to occur randomly, some near the outer or inner surface of the membrane (peripheral protein) and others penetrating the plasma membrane to varying degree (integral protein).
These membrane proteins perform many important functions:
- Contributing to the strength of the membrane
- Acting as enzyme
- Acting as carrier for transport of substances through the membrane
- Providing pores for the passage of water soluble substances through the membrane
- Acting as receptor.
In the fluid mosaic model of the plasma membrane, the lipids are visualized as constituting a sea with protein icebergs floating on it. According to this model, plasma membrane is a dynamic structure, in which both lipids and proteins are in constant motion. The rapidity of this motion depends on the composition of the fatty acid chains, temperature, and other factors.
The plasma membrane appears to be asymmetrical. The lipid composition varies from cell to cell type and from site to site on the same membrane. There are even structural differences between the membrane of the endoplasmic reticulum and the plasma membrane. The outer and inner layers also differ.
The plasma membrane is a semi-permeable membrane allowing certain chemical substances to pass freely, others to pass with difficulty and still others to exclude almost entirely from passage. For example, it allows passage of water molecules easily. It also allows glucose to cross. But it does not allow the passage of sucrose through membrane until it is converted into glucose and fructose.
The plasma membrane appears to be perforated by water filled pores of various sizes, ranging from 4 to 10 Å. The vascular endothelium appears to have pores as large as 40 Å. Calcium and sodium channels are the large globular proteins that traverse the membrane. Like pore size, pore distribution is not uniform between different parts of the body.
Simple diffusion, facilitated diffusion and active transport can also be explained in a simpler manner by giving examples like:
When you want to slide down a stone from a higher place, it will reach the lower level at a certain rate (simple diffusion).
But when that stone is at first placed on a 4-wheel container and then allowed it to fall, it will fall a bit rapidly. This is an example of facilitated diffusion.
In case of active transport, we can compare it with a 4-wheel engine cart containing a stone that moves upward.
Different modes of biotransport of drugs
The passage of drug across the biological membranes involves:
- Simple diffusion
- Facilitated diffusion
- Active transport
- Ion-pair transport.
Simple (passive) diffusion means the spontaneous movement of a solute through a biological barrier from the phase of higher concentration to the phase of lower concentration.
The process requires no direct expenditure of energy by the biological system.
It is the commonest, less rapid and most important process of absorption since most of the drugs are either weak acids or weak bases which mostly remain in nonionized and lipid soluble form.
Simple diffusion shows first-order kinetics. The rate of transfer of drug across the membrane can be described by Fick’s first law of diffusion:
where D is the diffusion coefficient, A is the surface area, x is the membrane thickness, and (Ch-Cl) is the concentration difference.
Diffusion coefficient is related to the size and lipid/water partition coefficient of the drug and the viscosity of the diffusion membrane (the membrane). As the lipid/water partition coefficient increases or molecular size decreases then D increases and thus dM/dt also increases. As the surface area increases the rate of diffusion also increases. The smaller the membrane thickness, the quicker is the diffusion process. For example, the membrane in the alveoli is quite thin thus inhalation absorption is quite rapid.
The drugs that cross the membrane by simple diffusion include aspirin, barbiturates, sulfonamides, morphine, and pethidine.
Filtration is the process by which water soluble drug of relatively low molecular weight crosses the plasma membrane through pores as a result of hydrodynamic pressure gradient across the membrane.
The glomerular membrane of the kidney is a good example of a filtering membrane. Glomerulus can be considered as filter placed in the funnel. Bowman’s capsule can be compared as funnel.
The rate of filtration is dependent on:
- The extent of concentration gradient,
- Filtering force,
- The size of the drug molecule relative to the size of the pore through which it is to be filtered.
The diameter of the pore is about 7 Å which allows the passage of compounds of molecular weight less than 100 daltons, e.g. urea (the diameter of the molecule is 3.6 Å) and ethylene glycol.
Certain substances with high molecular weight (e.g. proteins) appear to be filtered through intercellular channels rather than through the pores of the plasma membrane.
Facilitated diffusion means the passage of drug across the biological membrane along the concentration gradient by the protein carrier mediated transport system that shows saturability and selectivity.
At some point it is similar to simple diffusion and active transport while at other point it is dissimilar to simple diffusion or active transport.
It is also known as carrier-mediated diffusion. It requires no energy. Concentration gradient is the driving force for facilitated diffusion but when the binding sites on the carrier are completely saturated the increase in concentration gradient could no longer increase the transport rate.
The rate of transport is faster than by simple diffusion.
Tetracycline, pyrimidine, vitamin BI2 and glucose in muscle and adipocyte are the example of drugs that undergo facilitated diffusion.
Active transport is the process by which drugs pass across the biological membrane, most often against their concentration gradient with the help of carriers along with the expenditure of energy.
The most common sites for active transport are
- Neuronal membranes
- Choroid plexus
- Renal tubular cells
The active transport of a particular drug occurs in one direction only. Here, the drug molecule combines with a specific mobile carrier (protein) on one side of the membrane forming the drug-carrier complex. The complex then diffuses across the membrane to the opposite side, which then dissociates, and releases the drug. The carrier protein can then return to its initial site to bind more drugs.
The number of drug molecules carried per unit time is dependent on the concentration of carrier binding capacity. The rate of transport reaches its maximum when the binding capacity of the carrier becomes saturated.
Some drugs e.g. cyanide, fluoride or anaerobic condition may impair the active transport of a drug by inhibiting the production of adenosine triphosphate (ATP) since active transport requires energy.
The actively transported endogenous substances are sugar, amino acid, nucleic acid precursor, and iron.
The drugs having similarity to endogenous substance undergo active transports are a-methyldopa, levodopa, 5-fluorouracil, and 5-bromouracil.
Active transport may be primary and secondary:
Primary active transport:
ATP-mediated transport is the primary active transport.
Secondary active transport:
Secondary active transport includes:
- Symport (co-transport)
- Antiport (counter-transport).
In symport both solutes move in same direction e.g. Na+-sugar or Na+-amino acid transport in mammalian cells.
Antiport systems move 2 molecules in opposite directions e.g. Na+ in and K+ out.
Endocytosis is the process by which the large molecules are engulfed by the cell membrane and then released in the intracellular space.
Endocytosis requires energy and Ca2+ in extracellular fluid and contractile element i.e. microfilament system of the cell. It is independent of lipid solubility.
The substances normally absorbed by endocytosis include proteins, toxins (botulinum, diphtheria, and tetanus). These substances have high molecular weight (over 900 daltons).
The process of endocytosis is the most primitive mechanism for the ingestion of food. In the course of evolution the process was lost, but still it is found in newborn calf and disappears shortly.
The process can be divided into 2 major categories:
In phagocytosis (from the Greek phagin means to eat) there is uptake of drug particles that have been bound to membrane surface.
In case of pinocytosis (from the Greek pino, meaning drink, kytos, meaning hollow vessel, and osis, process), there is uptake in which the drug particle enters the cell as part of the fluid phase.
In ion-pair transport, the drug moves across the biological membrane despite its low lipid/water partition coefficient.
By this process some highly ionized compounds (e.g. quaternary ammonium compounds and sulfonic acids) are absorbed from the gastrointestinal tract.
The mechanism of ion-pair transport postulates that the highly ionized lipophobic drug combines reversibly with some endogenous substance such as mucin in the gastrointestinal lumen, forming a neutral ion-pair complex. The neutral complex then penetrates the membrane by simple diffusion.
This type of absorption is of little importance for drugs. Fat soluble vitamins such as A, D, E, K, and some anticancer drugs are absorbed by this method.
Along concentration gradient
Along concentration gradient
Against concentration gradient
Selectivity and saturability
Cannot block it
Cannot block it
Can block it
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Try to answer the following questions yourself:
1. What are the roles of plasma membrane proteins?
2. What do you mean by semi-permeable membrane? Give example.
3. What are the processes that account for the transfer of drug across plasma membrane? How do these processes differ from one another?
4. What are the factors that influence the rate of simple diffusion of a drug?
5. What are the characteristics of active transport?
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