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Biopharmaceutics – Drug Absorption – Part One – Passage of Drugs Across Cell Membranes

Key Ways For Drugs Across Cell Membranes

  • Passive Diffusion
  • Facilitated Diffusion
  • Active Transport

Passive Diffusion

Passive diffusion is the major absorption process for most drugs.

Theoretically, a lipophilic drug may pass through the cell or go around it. If the drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. Passive diffusion is the process by which molecules spontaneously diffuse from a region of higher concentration to a region of lower concentration. This process is passive because no external energy is expended. If the two sides around the cell membrane have the drug concentration, forward-moving drug molecules are balanced by molecules moving back, resulting in no net transfer of drug. When one side is higher in drug concentration at any given time, the number of forward-moving drug molecules will be higher than the number of backward-moving molecules; the net result will be a transfer of molecules to the alternate side downstream from the concentration gradient. The rate of transfer is called flux.

For passive diffusion,

Screen Shot 2016-01-07 at 9.41.57 PMwhere dQ/dt = rate of diffusion, D = diffusion coefficient, K = lipid-water partition coefficient of drug in the biologic membrane that controls drug permeation, A = surface area of membrane, h = membrane thickness, and CGICP = difference between the concentrations of drug in the gastrointestinal tract and in the plasma. Because the drug distributes rapidly into a large volume after entering the blood, the concentration of drug in the blood initially will be quite low with respect to the concentration at the site of drug absorption. For example, a drug is usually given in milligram doses, whereas plasma concentrations are often in the microgram-per-milliliter or nanogram-per-milliliter range. If the drug is given orally, then CGI >> CP and a large concentration gradient is maintained until most of the drug is absorbed, thus driving drug molecules into the plasma from the gastrointestinal tract.

Because D, A, K, and h are constants under usual conditions for absorption, a combined constant P of permeability coefficient may be defined. P = DAK/h. Furthermore, in Equation 13.1 the drug concentration in the plasma, Cp, is extremely small compared to the drug concentration in the gastrointestinal tract, CGI. If Cp is negligible and P is substituted into Equation 13.1, the following relationship for Fick's law is obtained: dQ/dt = P(CGI). This equation is an expression for a first-order process. In practice, the extravascular absorption of most drugs tends to be a first-order absorption process. Moreover, because of the large concentration gradient between CGI and CP, the rate of drug absorption is usually more rapid than the rate of drug elimination.

pH-Partition Hypothesis

Many drugs have both lipophilic and hydrophilic chemical substituents. Those drugs that are more lipid solube tend to traverse cell membranes more easily than less lipid-soluble or more water soluble molecules. For drugs that act as weak electrolytes, such as weak acids and bases, the extent of ionization influences the rate of drug transport. The ionized species of the drug contains a charge and is more water soluble than the nonionized species of the drug, which is more lipid soluble. The extent of ionization of a weak electrolyte will depend on both the pKa of the drug and the pH of the medium in which the drug is dissolved.

In a simple system, the total drug concentration on either side of a membrane should be the same at equilibrium, assuming Fick's law of diffusion is the only distribution factor involved. For diffusible drugs, such as nonelectrolyte drugs or drugs that do not ionize, the drug concentratons on either side of the membrane are the same at equilibrium. However, for electrolyte drugs or drugs that ionize, the total drug concentrations on either side of the membrane are not equal at equilibrium if the pH of the medium differs on respective sides of the membrane. According to the pH-partition hypothesis, if the pH on one side of a cell membrane differs from the pH on the other side of the membrane, then:

1.the drug (weak acid or base) will ionize to different degrees on respective sides of the membrane;

2.the total drug concentrations (ionized plus nonionized drug) on either side of the membrane will be unequal;

and

3.the compartment in which the drug is more highly ionized will contain the geater total drug concentration.

Affinity of Drug For A Tissue Component

This is another factor that can influence drug concentrations on either side of a membrane, which prevents the drug from moving freely back across the cell membrane. For example, a drug such as dicumarol binds to plasma protein, and digoxin binds to tissue protein. In each case, the protein-bound drug does not move freely across the cell membrane. Drugs such as chlordane are very lipid soluble and will partition into adipose tissue. In addition, a drug such as tetracycline might form a complex with calcium in the bones and teeth. Finally, a drug may concentrate in a tissue due to a specific uptake or active transport process. Such processes have been deminstrated for iodide in thyroid tissue, potassium in the intracellular water, and certain catecholamines into adrenergic storage sites. Such drugs may have higher total drug concentration on the side where binding occurs, yet the free drug concentration that diffuses across cell membranes will be the same on both sides of the membrane.

Instead of diffusing into the cell, drugs can also diffuse into the spaces around the cell as an absorption mechanism. In paracellular drug absorption, drug molecules smaller than 500 MW diffuse into the tight junctions, or spaces between intestinal epithelial cells.

Carrier-Mediated Transport

Theoretically, a lipophilic drug may either pass through the cell or go around it. If the drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. In the intestine, drugs and other molecules can go through the intestinal epithelial cells by either diffusion or a carrier-mediated mechanism. Numerous specialized carrier-mediated transport systems are present in the body, espeically in the intestine for the absorption of ions and nutrients required by the body.

Summary of Channels and Carriers

Channels (ligand-gated, voltage-gated, and stretch-gated)

Transporters (uniporters, symporters, antiporters, primary active transporters)

Reference: Basic Mechanisms of Renal Transepithelial Transport http://www.tomhsiung.com/wordpress/2015/10/basic-mechanisms-of-renal-transepithelial-transport/

Active Transport

Active transport is a carrier-mediated transmembrane process that plays an important role in the gastrointestinal absorption and in renal and biliary secretion of many drugs and metabolites. A few lipid-insoluble drugs that resemble natural physiologic metabolites are absorbed from the gastrointestinal tract by this process. Active transport is characterized by the ability to transport drug aganist a concentration gradient – that is, from regions of low drug concentrations to regions of high drug concentrations. Therefore, this is an energy-consuming system. In addition, active transport is a specialized process requiring a carrier that binds the drug to form a carrier-drug complex that shuttles the drug across the membrane and then dissociates the drug on the other side of the membrane.

The carrier molecule may be highly selective for the drug molecule. If the drug structurally resembles a natural substrate that is actively transported, then it is likely to be actively transported by the same carrier mechanism. Therefore, drugs of similar structure may compete for sites of absorption on the carrier. Furthermore, because only a fixed number of carrier molecules are available, all the binding sites on the carrier may become saturated if the drug concentration gets very high.

Check Point: saturated, competition

Facilitated Diffusion

Facilitated diffusion is also a carrier-mediated transport system, differing from active transport in that the drug moves along a concentration gradient. Therefore, this system does not require energy input. However, because this system is carrier mediated, it is saturable and structurally selective for the drug and shows competition kinetics for drugs of similar structure. In terms of drug absorption, facilitated diffusion seems to play a very minor role.

Transporters and Carrier-Mediated Intestinal Absorption

Various carrier-mediated system (transporters) are present at the intestinal brush border and basolateral membrane for the absorption of specific ions and nutrients essential for the body. Both influx and efflux transporters are present in the brush border and basolateral membrane.

Competitive Inhibition to and Activity of Carriers

Many agents (drug or chemical substances) may have dual roles as substrate (remember that carrier transportation could be saturated and competition exists between strucuture similar substrate) and/or inhibitor between CYP3A4 and P-glycoprotein, P-gp. Simultaneous administration of these agents results in an increase in the oral drug bioavailability of one or both of the drugs.

Vesicular Transport

Vesicular transport is the proposed process for the absorption of orally administered Sabin polio vaccine and various large proteins.

Pore Transport

Very small molecules (i.e., urea, water, and sugars) are able to cross cell membranes rapidly, as if the membrane contained channels or pores. Although such pores have never been directly observed by microscopy, the model of drug permeation through aqueous pores is used to explain renal excretion of drugs and the uptake of drugs into the liver. A certain type of protein called a transport protein may form an open channel across the lipid membrane of the cell. Small molecules including drugs move through the channel by diffusion more rapidly than at other parts of the membrane.

One Comment

  1. Cell membrane consist of:

    1.Lipids

    2.Proteins

    3.Channels: mechanosensitive, voltage-sensitive, and chemosensitive channels; water channels; cell-cell channels.

    4.Pumps

    5.Transporters: uniporters, symporters, and antiporters, primary active transporters, and secondary active transporters.

    6.Receptors

    Channels control transport or flow of substrates by gating mechanisms, whereas transporters bind to their substrates and undergo a conformational change to transport the substrate across a membrane.

    Posted on 30-Mar-16 at pm 3:56 | Permalink

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