Chapter 11

Physiological Factors Affecting Oral Absorption

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Membrane physiology

Membrane structure

In 1900 Overton performed some simple but classic experiments related to cell membrane structure. By measuring the permeability of various types of compounds across the membranes of a frog muscle he found that lipid molecules could readily cross this membrane, larger lipid insoluble molecules couldn't and small polar compounds could slowly cross the membrane. He suggested that membranes were similar to lipids and that certain molecules (lipids) moved across membranes by dissolving in the membrane.

These results suggest that the biologic membrane is mainly lipid in nature but contains small aqueous channels or pores.

Figure 11.2.1 Lipid Bilayer

Other experiments involving surface tension measurements have suggested that there is also a layer of protein on the membrane. These results and others have been incorporated into a general model for the biological membrane. This is the Davson-Danielli model (1935).

Figure 11.2.2 The Davson-Danielli Model

Later work (Danielli, 1975) suggested the presence of "active patches" and protein lining to pores in the membrane.

Figure 11.2.3 Modified Davson-Danielli Model

Work during the 1970s and 1980s suggested the model proposed by Singer and Nicolson 1972 called the fluid mosaic model. With this model the lipid bilayer is retained but the protein drifts between the lipid rather than forming another layer on either side of the lipid bilayer.

Figure 11.2.4 The Fluid Mosaic Model

The membrane then acts as a lipid barrier with protein formed pores. The protein within the membrane can act transport enhancers in either direction depending on the protein.

The barriers between various organs, tissues and fluids areas will consist of cells of different structure and membranes characteristics. In some cases the cells are loosely attached with extracellular fluid freely moving between the cells. Drugs and other compounds, lipid or not, may freely move across this barrier.

Figure 11.2.5 Loosely Attached Cell Barrier

In other cases there may be tight junctions between the cells which will prevent non lipid movement.

Figure 11.2.6 Cell Barrier with Tight Junctions

These are general structures of the cellular layer. Layers in different parts of the body have somewhat different characteristics which influence drug action and distribution. In particular, membrane protein form and function, intracellular pore size and distribution is not uniform between different parts of the body.

Examples of some barrier types.

Blood-brain barrier. The cellular barrier between the blood and brain have very tight junctions effectively eliminating transfer between the cells. Additionally there are specific transport mechanisms, such as P-glycoproteins which actively causes the removal of drugs and other compounds from the brain. This will prevent many polar (often toxic materials) materials from entering the brain. However, smaller lipid materials or lipid soluble materials, such as diethyl ether, halothane, can easily enter the brain across the cellular membrane. These compounds are used as general anesthetics.

Renal tubules. In the kidney there are a number of regions important for drug elimination. In the tubules drugs may be reabsorbed. However, because the membranes are relatively non-porous, only lipid compounds or non-ionized species (dependent of pH and pKa) are reabsorbed.

Hepatic blood vessels. The capillaries are lined with a basement membrane broken in part by sinusoids and fenestrations interspersed with cells held together with tight junctions. The result is a barrier that allows considerable transfer between the blood and hepatocytes.

Blood capillaries and renal glomerular membranes. These membranes are quite porous allowing non-polar and polar molecules (up to a fairly large size, just below that of albumin, M.Wt 69,000) to pass through. This is especially useful in the kidney since it allows excretion of polar (drug and waste compounds) substances.

Transport across the membranes

Carrier mediated

Figure 11.2.7 Carrier-Mediated Transport Process

Redrawn from Shargel, L. and Yu, A.B.C. 1985
Applied Biopharmaceutics and Pharmacokinetics,
2nd ed., Appleton-Century-Crofts, Norwalk, CT

Active

The body has a number of specialized mechanisms for transporting particular compounds; for example, glucose and amino acids. Sometimes drugs can participate in this process; e.g. 5-fluorouracil. Active transport requires a carrier molecule and a form of energy.

Facilitated

A drug carrier is required but no energy is necessary. e.g. vitamin B12 transport.

P-glycoprotein

P-glycoprotein transporters (PGP, MDR-1) are present throughout the body including liver, brain, kidney and the intestinal tract epithelia. They appear to be an important component of drug absorption acting as reverse pumps generally inhibiting absorption. This is an active, ATP-dependent process which can have a significant effect on drug bioavailability. P-glycoprotein works against a range of drugs (250 - 1850 Dalton) such as cyclosporin A, digoxin, β-blockers, antibiotics and others. This process has been described as multi-drug resistance (MDR). Additionally P-glycoprotein has many substrates in common with cytochrome P450 3A4 (CYP 3A4) thus it appears that this system not only transports drug into the lumen but causes the metabolism of substantial amounts of the drug as well (e.g. cyclosporin).

Clinically significant substrates of PGP include digoxin, cyclosporine, fexofenadine, paclitaxel, tracrolimus, nortriptyline and phenytoin (Humma 2003). A number of compounds can act as PGP inhibitors including atorvastatin (digoxin AUC increased), cyclosporine (increased paclitaxel absorption), grapefruit juice (increased paclitaxel absorption) and verapamil. Rifampin and St. John's wort have been reported to induce PGP expression (Ritschel and Kearns, 2004).

The distribution of PGP polymorphism varies by race. The 'normal' 3435C allele is found in 61% African American and 26% in European American. The clinically important 3435T polymorph is found in 13% of African American and 62% of European American. The 3435T allele has been associated with reduced PGP expression (concentration) and consequently higher absorption. Digoxin levels were higher in healthy subjects with the 3435T allele compared with results in subjects with the 3435C allele (Humma, 2003).

Passive

Figure 11.2.8 Diagram of Passive Transport with a Concentration Gradient

Most (many) drugs cross biologic membranes by passive diffusion. Diffusion occurs when the drug concentration on one side of the membrane is higher than that on the other side. Drug diffuses across the membrane in an attempt to equalize the drug concentration on both sides of the membrane.

If the drug partitions into the lipid membrane a concentration gradient can be established.

The rate of transport of drug across the membrane can be described by Fick's first law of diffusion:-

Equation 11.2.1 Fick's First Law, Rate of Diffusion

The parameters of this equation are:-

D: diffusion coefficient. This parameter is related to the size and lipid solubility of the drug and the viscosity of the diffusion medium, the membrane. As lipid solubility increases or molecular size decreases then D increases and thus dM/dt also increases.

A: surface area. As the surface area increases the rate of diffusion also increase. The surface of the intestinal lining (with villae and microvillae) is much larger than the stomach. This is one reason absorption is generally faster from the intestine compared with absorption from the stomach.

x: membrane thickness. The smaller the membrane thickness the quicker the diffusion process. As one example, the membrane in the lung is quite thin thus inhalation absorption can be quite rapid.

(Ch -Cl): concentration difference. Since V, the apparent volume of distribution, is at least four liters and often much higher the drug concentration in blood or plasma will be quite low compared with the concentration in the GI tract. It is this concentration gradient which allows the rapid complete absorption of many drug substances.

Normally Cl << Ch then:-

Thus the absorption of many drugs from the G-I tract can often appear to be first-order.

Pinocytosis

Larger particles are not able to move through membranes or interstitial spaces so other processes must be available. These processes involve the entrapment of larger particles by the cell membrane and incorporation into the cell, cytosis. A spontaneous incorporation of a small amount of extracellular fluid with solutes is called pinocytosis. Phagocytosis is a similar process involving the incorporation of larger particles. Examples include Vitamin A, D, E, and K, peptides in newborn.

Figure 11.2.9 Illustration of Different Transport Mechanisms


References

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