Transcript
0:00Absorption and permeability
Lesson 2.2 of our absorption module: crossing the gut wall. Absorption is the movement of a drug from the place where it is given into the blood. After an oral dose, a dissolved drug must cross the gut wall, mainly in the small intestine. The inner surface of the gut wall faces the lumen, the space inside the gut. This surface is a single layer of cells, and most of them are enterocytes, the cells that absorb nutrients and drugs. Tight junctions, bands of protein near the lumen side of the cells, close the gaps between adjacent enterocytes. The fraction of the dose that enters the enterocytes is the fraction absorbed, Fa. Permeability is the rate at which a drug crosses a barrier for each unit of area and each unit of concentration difference. Its unit is centimeters per second. The Biopharmaceutics Classification System, or BCS, places a drug in one of four classes by its solubility and its permeability. In the BCS, a drug is highly permeable when Fa in humans is 85 percent or more.
1:23Passive diffusion
A drug can cross the gut wall by three main routes. The first is passive diffusion through the cells, the transcellular route. The drug dissolves in the lipid membrane of the enterocyte and moves from high to low concentration. It crosses the membrane that faces the lumen, moves through the cell, and then crosses the membrane that faces the blood. Lipophilic molecules, which dissolve well in the lipids of the membrane, cross mainly in this way. Many drugs are weak acids or weak bases, which exist in the gut fluid in a neutral form and a charged form. The neutral form crosses the lipid membrane much faster than the charged form. For a drug with one ionizable group, the pKa is the pH at which half of its molecules carry a charge. The pH-partition hypothesis assumes that only the neutral form crosses the membrane. This is a simplification, because the charged form also crosses, but more slowly.
2:37The paracellular route
The second route is between the cells, the paracellular route. Hydrophilic drugs dissolve well in water. The tight junctions let small hydrophilic drugs through and restrict larger hydrophilic molecules. Some absorption enhancers, substances added to a formulation, open the junctions for a short time. They can increase the absorption of larger molecules, for example therapeutic proteins.
3:09Transporters
The third route uses transporters, proteins in the cell membrane that carry nutrients and other natural substances. Some drugs use them too. Uptake transporters carry drugs into the cell, and efflux transporters pump drugs out of the cell. PEPT1 is an uptake transporter for peptides in the membrane that faces the lumen. The efflux transporters P-glycoprotein, or P-gp, and BCRP, the breast cancer resistance protein, pump drugs back into the lumen. They use energy from ATP, the molecule that stores energy in the cell. For drugs that P-gp or BCRP pump, efflux can lower the fraction absorbed and the oral bioavailability. Oral bioavailability is the fraction of the dose that reaches the systemic circulation unchanged, after the drug passes through the gut wall and the liver. P-gp and BCRP are more abundant in the jejunum and ileum, the middle and last parts of the small intestine, than in the colon.
4:27Caco-2 permeability
Many laboratories measure permeability in Caco-2 cells, which come from a human colon tumor. On a filter, they grow into a single layer that resembles the gut lining. One study compared the permeability of 20 drugs and peptides in Caco-2 cells with their absorption in humans. Drugs with complete absorption had a permeability above 1 times 10 to the minus 6 centimeters per second. Drugs and peptides with less than 1 percent absorption had 1 times 10 to the minus 7 centimeters per second or less. Talinolol shows the effect of P-gp in the gut wall.
5:12Talinolol and rifampin
Talinolol is a beta-1 blocker, a drug that lowers heart rate and blood pressure, and P-gp pumps it out of cells. Rifampin, an antibiotic, increases the amount of many drug-metabolizing enzymes and of P-gp, particularly in the gut wall. Because the body metabolizes very little talinolol, a change in its exposure after rifampin mainly shows the change in P-gp. In one study, eight healthy men took talinolol before rifampin and again during rifampin, 600 milligrams a day for 9 days. Each time, they took talinolol by mouth for 7 days and received one intravenous dose. Rifampin raised the amount of P-gp in the duodenum, the first part of the small intestine, 4.2-fold. The AUC is the area under the concentration-time curve, a measure of exposure. During rifampin, the AUC of oral talinolol was 35 percent lower than before, and the AUC of intravenous talinolol was 21 percent lower. A lower AUC after the intravenous dose means that the body removed talinolol from the blood faster. Clearance is the volume of plasma from which the body removes all of the drug in a unit of time. The study took biopsies, small tissue samples, from the duodenum. The higher the P-gp content of a biopsy, the higher the clearance of intravenous talinolol. These results suggest that P-gp in the gut wall also pumps talinolol from the blood into the lumen.
7:07Summary
In summary, the neutral form of a dissolved drug diffuses through the enterocytes, and small hydrophilic drugs pass between them. PEPT1 carries some drugs into the enterocyte, and P-gp and BCRP pump some drugs back into the lumen. When rifampin raised gut-wall P-gp 4.2-fold, the AUC of oral talinolol fell by 35 percent. For drugs that P-gp pumps, the amount of P-gp in the gut wall therefore changes the exposure after an oral dose. This concludes lesson 2.2 on crossing the gut wall.
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Illustrations adapted from Servier Medical Art (smart.servier.com), CC BY 4.0. Structures drawn with RDKit.
