Rate-Limiting Steps in Drug Absorption
Disintegration of the drug product and subsequent release of the drug (rate-limiting step)
Dissolution of the drug in an aqueous environment (rate-limiting step)
Absorption across the cell membranes into the systemic circulation (rate-limiting step)
Physiochemical Factors that Affect Drug Absorption
Drug disintegration (rate-limiting step)
Drug dissolution (rate-limiting step)
Drug across the cell membrane (rate-limiting step)
Drug stability (loss of drug due to decomposition)
Drug particle size (drug particle surface area, affecting dissolution)
Drug polymorphism (affecting dissolution)
Drugs may be absorbed by passive diffusion from all parts of the alimentary canal (oral cavity, esophagus, stomach, duodenum, jejunum, ileum, colon, and rectum). For most drugs, the optimum site for drug absorption after oral administration is the upper portion of the small intestine or duodenum region (remember factors determining the diffusion rate, including P = permeability, 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 CGI – CP = difference between the concentrations of drug in the gastrointestinal tract and in the plasma; in addition the abundant capillary distribution in this region helps maintain a concentration gradient from the intestinal lumen and plasma circulation).
P = DAK/h
dQ/dt = P(CGI – CP) ≈ P(CGI)
Key factors must be considered in drug absorption include gastrointestinal motility, gastric emptying time, intestinal motility, perfusion of the gastrointestinal tract, drug-drug and food-drug interactions (GI CYP3A4 and P-gp), and finally effect of food on gastrointestinal drug absorption.
Physicochemical Nature of The Drug and Absorption
Solubility, pH, and Drug Absorption
The solubility-pH profile is a plot of the solubility of the drug at various physiologic pH values. In designing oral dosage forms, the formulator must consider that the natural pH environment of the gastrointestinal tract varies from acidic in the stomach to slightly alkaline in the small intestine. A basic drug is more soluble in an acidic medium, forming a soluble salt. Conversely, and acid drug is more soluble in the intestine, forming a soluble salt at the more alkaline pH. The solubility-pH profile gives a rough estimation of the completeness of dissolution for a dose of a drug in the stomach or in the small intestine. Solubility may be improved with the addition of an acidic or basic excipient. Solubilization of aspirin, for example, may be increased by the addition of an alkaline buffer.
In the formulation of controlled-release drugs, buffering agents may be added to slow or modify the release rate of a fast-dissolving drug. To be effective, however, the controlled-release drug product must be a nondisintegrating dosage form. The buffering agent is released slowly rather than rapidly, so that the drug does not dissolve immediately in the surrounding gastrointestinal fluid.
Stability, pH, and Drug Absorption
The stability-pH profile is a plot of the reaction rate constant for drug degradation versus pH. If drug decomposition occurs by acid or base catalysis, some prediction of degradation of the drug in the gastrointestinal tract may be made. For example, erythromycin has a pH-dependent stability profile. In acidic medium, as in the stomach, erythromycin decomposition occurs rapidly, whereas in neutral or alkaline pH, the drug is relatively stable. Consequently, erythromycin tablets are enteric coated to protect against acid degradation in the stomach. This information also led subsequently to the preparation of a less water-solube erythromycin salt that is more stable in the stomach.
Particle Size and Drug Absorption
The effective surface area of a drug is increased enormously by a reduction in the particle size. Because dissolution takes place at the surface of the solute (drug), the greater the surface area, the more rapid the rate of drug dissolution. The geometric shape of the particle also affects the surface area, and, during dissolution, the surface is constantly changing.
Smaller particle size results in an increase in the total surface area of the particles, enhances water penetration into the particles, and increases the dissolution rate.
Polymorphism, Solvates, and Drug Absorption
Polymorphism refers to the arrangement of a drug substance in varioius crystal forms or polymorphs. Polymorphs have the same chemical structure but different physical properties, such as solubility, density, hardness, and compression characteristics. Some polymorphic crystals have much lower aqueous solubility than the amorphous forms, causing a product to be incompletely absorbed.
Excipients and Drub Absorption
Excipients are added to a formulation to provide certain functional properties to the drug and dosage form; excipients also affect drug product performance, in vivo. Some of these functional properties of the excipients are used to improve the compressibility of the active drug, stabilize the drug against degration, decrease gastric irritation, control the rate of drug absorption from the absorption site, increase drug bioavailability, etc.
Eexicipents in the drug product may also affect the dissolution kinetics of the drug, either by altering the medium in which the drug is dissolving or by reacting with the drug itself. Other excipients include suspending agents that increase the viscosity of the drug vehicle and thereby diminish the rate of drug dissolution from suspensions. Tablet lubricants, such as magnesium stearate, may repel water and reduce dissolution when used in large quantities. Coatings, particularly shellac, will crosslink upon aging and decrease the dissolution rate. Surfactants may affect drug dissolution in an unpredictable fashion. Low concentrations of surfactants decrease the surface tension and increase the rate of drug dissolution, whereas higher surfactants concentrations tend to form micelles with the drug and thus decrease the dissolution rate. Poor disintegration of a compressed tablet may be due to high compression of tablets without sufficient disintegrant.
Some excipients may change the pH of the medium surrounding the active drug substance. Aspirin, a weak acid when formulated with sodium bicarbonate, will form a water-soluble salt in an alkaline medium, in which the drug rapidly dissolves. This process is called dissolution in a reactive medium. The solid drug dissolves rapidly in the reative solvent surrounding the solid particle. However, as the dissolved drug molecules diffuse outward into the bulk solvent, the drug may precipitate out of solution with a very fine particle size. These small particles have enormous collective surfacea area, dispersing and redissolving readily for more rapid absorption upon contact with the mucosal surface.
Excipients in a formulation may interact directly with the drug to form a water-soluble or water-insoluble complex. For example, if tetracycline is formulated with calcium carbonate, an insoluble complex of calcium tetracycline is formed that has a slow rate of dissolution and poor absorption.
PS: Rules for Drug Molecules That Would Improve the Chance for Oral Absorption
Molecular weight =<500 Da
Not more than five H-bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
Not more than 10 H-bond acceptors (nitrogen or oxygen atoms)
An octanol-water partition coefficient, log P =<5.0
Factors that Affect Bioavailability of Oral Route
Drug given by the enteral route for systemic absorption may be affected by the anatomy, physiologic functions, and contents of the alimentary tract. Moreover, the physical, chemical, and pharmacologic properties of the drug and the formulation of the drug product will also affect systemic drug absorption from the alimentary canal.
Site of absorption (absorption window)
Fluid volume in the lumen
Stomach emptying (delayed by meals high in fat, cold beverages, and anticholinergic drugs [liquids and small particles less than 1 mm are generally not retained in the stomach])
Gastrointestinal motility/transit time
villi and microvilli
GI perfusion/blood flow and lymph circulation
First pass effect/prodrug
Gastrointestinal contents (e.g., food, beverage) and their effect on stomach empty, GI's pH, drugs' solubility, bile secretion, splanchnic blood flow, stability of drugs, and physical or chemical interaction with drugs
Anatomy – Site of Absorption, and Factors That Should Be Considered
Oral cavity: pH 7; fluid volume; ptyalin; mucin.
Esophagus: pH 5-6; fluid volume; ptyalin; mucin.
Stomach: pH (ANS; fasting or fed status; drugs; etc.); emptying (ANS; fasting or fed status; food type; osmolality; drugs; etc.); fluid volume; enzymes (pepsin, ptyalin); mucin; mixing; coabsorption factor (like VB12).
Duodenum: major site for passive drug absorption; pH 6-6.5; enzymes (pancreatic trypsin, pancreatic chymotrypsin, pancreatic carboxypeptidase, pancreatic amylase, pancreatic lipase, stomachic pepsin [inactive due to high pH of 5 above], ptyalin); fluid volume; mucin; bile;
Jejunum: same as above.
Ileum: same as above except for pH of 7-8.
Colon: limited drug absorption due to lack of villi, blood flow, and viscous and semisolid nature of the lumen contents. pH 5.5-7. Aerobic and anaerobic microorganisms that metabolize some drugs.
Rectum: lack of fluid (approximately 2 mL). pH of about 7.
Once a drug is given orally, the exact location and/or environment of the drug product within the GI tract is difficult to discern. GI motility tends to move the drug through the alimentary canal, so the drug may not stay at the absorption site. For drugs given orally, an anatomic absorption window may exist within the GI tract in which the drug is efficiently absorbed. The transit time of the drug in the GI tract depends on the physicochemical and pharmacologic properties of the drug, the type of dosage form, and various physiologic factors. Movement of the drug within the GI tract depends on whether the alimentary canal contains recently ingested food or is in the fasted or interdigestive state.
Gastric Emptying Time
Anatomically, a swallowed drug rapidly reaches the stomach. Eventually, the stomach empties its contents into the small intestine. Because the duodenum has the greatest capacity for the absorption of drugs from the GI tract, a delay in the gastric emptying time for the drug to reach the duodenum will slow the rate and possibly the extent of drug absorption, thereby prolonging the onset time for the drug.
A number of factors affect gastric emptying time. Some factors that tend to delay gastric emptying include consumption of meals high in fat, cold beverages, and anticholinergic drugs. Liquids and small particles less than 1 mm are generally not retained in the stomach. These small particles are believed to be emptied due to a slightly higher basal pressure in the stomach over the duodenum (i.e., fine granules smaller than 1 to 2 mm in size and tablets that disintegrate are not significantly delayed from emptying from the stomach in the presence of food).Different constituents of a meal empty from the stomach at different rates. Large particles, including tablets and capsules, are delayed from emptying for 3 to 6 hours by the presence of food in the stomach. Indigestible solids empty very slowly, probably during the interdigestive phase, a phase in which food is not present and the stomach is less motile but periodically empties its content.
Normal peristaltic movements mix the contents of the duodenum, bringing the drug particles into intimate contact with the intestinal mucosal cells. The drug must have a sufficient time (residence time) at the absorption site for optimum absorption. In the case of high motility in the intestinal tract, as in diarrhea, the drug has very brief residence time and less opportunity for adequate absorption.
The average normal small intestine transit time (SITT) was about 7 hours as measured in early studies while newwer studies have shown SITT to be about 3 to 4 hours. Thus a drug may take about 4 to 8 hours to pass through the stomach and small intestine during the fasting state. For modified-release or controlled-dosage forms, which slowly release the drug over an extended period of time, the dosage form must stay within a certain segment of the intestinal tract (anatomic absorption window) so that the drug contents are released and absorbed before loss of the dosage form in the feces.
Perfusion of the Gastrointestinal Tract (blood and lymph)
The blood flow to the GI tract is important in carrying abosrbed drug to the systemic circulation. A large network of capillaries and lymphatic vessels perfuse the duodenal region and peritoneum. Any decrease in mesenteric blood flow will decrease the rate of drug removal from the intestinal tract, thereby reducing the rate of drug bioavailability.
Absorption of drugs through the lymphatic system bypasses the first-pass effect due to liver metabolism.
Effect of Food on Gastrointestinal Drug Absorption
Delay in gastric emptying (especially fatty foods)
Stimulation of bile flow
A change in the pH of the GI tract
An increase in splanchnic blood flow
A change in luminal metabolism of the drug substance
Physical or chemical interaction of the meal with the drug product or drug substance
Dosage form failures (food affect the integrity of the dosage form)
Timing of drug administration in relation to meals is often important. Pharmacists regularly advise patients to take a medication either 1 hour before or 2 hours after meals to avoid any delay in drug absorption. But since fatty foods may delay stomach emptying time beyond 2 hours, patients who have just eaten a heavy, fatty meal should take related drugs 3 hours or more after the meal, whenever possible.
The presence of food in the GI tract can affect the bioavailability of the drug rom an oral drug product. Digested foods contain amino acids, fatty acids, and many nutrients that may affect intestinal pH and solubility of drugs. The effect of food are not always predictable and can have clinically significant consequences.
Food effects on bioavailability are generally greatest when the drug product is administered shortly after a meal is ingested. The nutrient and caloric contents of the meal, the meal volume, and the meal temperature can cause physiologic changes in the GI tract in a way that affects drug product transit time, luminal dissolution, drug permeability, and systemic availability. In general, meals that are high in total calories and fat content are more likely to affect GI physiology and thereby result in a larger effect on the bioavailability of a drug substance or drug product.
Check Point: anatomic absorption window, residence time, mesenteric blood flow, lymphatic system