Drug Absorption　
Process of drug movement from the administration site to the systemic circulation.　
Drug absorption is determined by physicochemical properties of drugs, their formulations, and routes of administration. Drug products--the actual dosage forms （eg, tablets, capsules, solutions）, consisting of the drug plus other ingredients--are formulated to be administered by various routes, including oral, buccal, sublingual, rectal, parenteral, topical, and inhalational. A prerequisite to absorption is drug dissolution. Solid drug products （eg, tablets） disintegrate and deaggregate, but absorption can occur only after drugs enter solution.　
Transport Across Cell Membranes　
When given by most routes （excluding IV）, a drug must traverse several semipermeable cell membranes before reaching the systemic circulation. These membranes are biologic barriers that selectively inhibit the passage of drug molecules and are composed primarily of a bimolecular lipid matrix, containing mostly cholesterol and phospholipids. The lipids provide stability to the membrane and determine its permeability characteristics. Globular proteins of various sizes and composition are embedded in the matrix; they are involved in transport and function as receptors for cellular regulation. Drugs may cross a biologic barrier by passive diffusion, facilitated passive diffusion, active transport, or pinocytosis.　
Passive diffusion: In this process, transport across a cell membrane depends on the concentration gradient of the solute. Most drug molecules are transported across a membrane by simple diffusion from a region of high concentration （eg, GI fluids） to one of low concentration （eg, blood）. Because drug molecules are rapidly removed by the systemic circulation and distributed into a large volume of body fluids and tissues, drug concentration in blood is initially low compared with that at the administration site, producing a large gradient. 　
The diffusion rate is directly proportional to the gradient but also depends on the molecule's lipid solubility, degree of ionization, and size and on the area of the absorptive surface. Because the cell membrane is lipoid, lipid-soluble drugs diffuse more rapidly than relatively lipid-insoluble drugs. Small molecules tend to penetrate membranes more rapidly than large ones.　
Most drugs are weak organic acids or bases, existing in un-ionized and ionized forms in an aqueous environment. The un-ionized form is usually lipid soluble and diffuses readily across cell membranes. The ionized form cannot penetrate the cell membrane easily because of its low lipid solubility and high electrical resistance, resulting from its charge and the charged groups on the cell membrane surface. Thus, drug penetration may be attributed mostly to the un-ionized form. Distribution of an ionizable drug across a membrane at equilibrium is determined by the drug's pKa （the pH at which concentrations of un-ionized and ionized forms of the drug are equal） and the pH gradient, when present. For a weak acid, the higher the pH, the lower the ratio of un-ionized to ionized forms. In plasma （pH, 7.4）, the ratio of un-ionized to ionized forms for a weak acid （eg, with a pKa of 4.4） is 1:1000; in gastric fluid （pH, 1.4）, the ratio is reversed （1000:1）. When the weak acid is given orally, the concentration gradient for un-ionized drug between stomach and plasma tends to be large, favoring diffusion through the gastric mucosa. 　
At equilibrium, the concentrations of un-ionized drug in the stomach and in the plasma are equal because only un-ionized drug can penetrate the membranes; the concentration of ionized drug in the plasma would then be about 1000 times greater than that in the stomach. For a weak base with a pKa of 4.4, the outcome is reversed. Thus theoretically, weakly acidic drugs （eg, aspirin） are more readily absorbed from an acid medium （stomach） than are weak bases （eg, quinidine）. However, whether a drug is acidic or basic, most of its absorption occurs in the small intestine.　
Facilitated passive diffusion: For certain molecules （eg, glucose）, the rate of membrane penetration is greater than expected from their low lipid solubility. One theory is that a carrier component combines reversibly with the substrate molecule at the cell membrane exterior, and the carrier-substrate complex diffuses rapidly across the membrane, releasing the substrate at the interior surface. Carrier-mediated diffusion is characterized by selectivity and saturability: The carrier transports only substrates with a relatively specific molecular configuration, and the process is limited by the availability of carriers. The process does not require energy expenditure, and transport against a concentration gradient does not occur.　　
Active transport: This process is characterized by selectivity and saturability and requires energy expenditure by the cell. Substrates may accumulate intracellularly against a concentration gradient. Active transport appears to be limited to drugs structurally similar to endogenous substances. These drugs are usually absorbed from sites in the small intestine. Active transport processes have been identified for various ions, vitamins, sugars, and amino acids .　
Pinocytosis: Fluid or particles are engulfed by a cell. The cell membrane invaginates, encloses the fluid or particles, then fuses again, forming a vesicle that later detaches and moves to the cell interior. This mechanism also requires energy expenditure. Pinocytosis probably plays a minor role in drug transport, except for protein drugs.　
Process of drug movement from the administration site to the systemic circulation.　
Drug absorption is determined by physicochemical properties of drugs, their formulations, and routes of administration. Drug products--the actual dosage forms （eg, tablets, capsules, solutions）, consisting of the drug plus other ingredients--are formulated to be administered by various routes, including oral, buccal, sublingual, rectal, parenteral, topical, and inhalational. A prerequisite to absorption is drug dissolution. Solid drug products （eg, tablets） disintegrate and deaggregate, but absorption can occur only after drugs enter solution.　
Transport Across Cell Membranes　
When given by most routes （excluding IV）, a drug must traverse several semipermeable cell membranes before reaching the systemic circulation. These membranes are biologic barriers that selectively inhibit the passage of drug molecules and are composed primarily of a bimolecular lipid matrix, containing mostly cholesterol and phospholipids. The lipids provide stability to the membrane and determine its permeability characteristics. Globular proteins of various sizes and composition are embedded in the matrix; they are involved in transport and function as receptors for cellular regulation. Drugs may cross a biologic barrier by passive diffusion, facilitated passive diffusion, active transport, or pinocytosis.　
Passive diffusion: In this process, transport across a cell membrane depends on the concentration gradient of the solute. Most drug molecules are transported across a membrane by simple diffusion from a region of high concentration （eg, GI fluids） to one of low concentration （eg, blood）. Because drug molecules are rapidly removed by the systemic circulation and distributed into a large volume of body fluids and tissues, drug concentration in blood is initially low compared with that at the administration site, producing a large gradient. 　
The diffusion rate is directly proportional to the gradient but also depends on the molecule's lipid solubility, degree of ionization, and size and on the area of the absorptive surface. Because the cell membrane is lipoid, lipid-soluble drugs diffuse more rapidly than relatively lipid-insoluble drugs. Small molecules tend to penetrate membranes more rapidly than large ones.　
Most drugs are weak organic acids or bases, existing in un-ionized and ionized forms in an aqueous environment. The un-ionized form is usually lipid soluble and diffuses readily across cell membranes. The ionized form cannot penetrate the cell membrane easily because of its low lipid solubility and high electrical resistance, resulting from its charge and the charged groups on the cell membrane surface. Thus, drug penetration may be attributed mostly to the un-ionized form. Distribution of an ionizable drug across a membrane at equilibrium is determined by the drug's pKa （the pH at which concentrations of un-ionized and ionized forms of the drug are equal） and the pH gradient, when present. For a weak acid, the higher the pH, the lower the ratio of un-ionized to ionized forms. In plasma （pH, 7.4）, the ratio of un-ionized to ionized forms for a weak acid （eg, with a pKa of 4.4） is 1:1000; in gastric fluid （pH, 1.4）, the ratio is reversed （1000:1）. When the weak acid is given orally, the concentration gradient for un-ionized drug between stomach and plasma tends to be large, favoring diffusion through the gastric mucosa. 　
At equilibrium, the concentrations of un-ionized drug in the stomach and in the plasma are equal because only un-ionized drug can penetrate the membranes; the concentration of ionized drug in the plasma would then be about 1000 times greater than that in the stomach. For a weak base with a pKa of 4.4, the outcome is reversed. Thus theoretically, weakly acidic drugs （eg, aspirin） are more readily absorbed from an acid medium （stomach） than are weak bases （eg, quinidine）. However, whether a drug is acidic or basic, most of its absorption occurs in the small intestine.　
Facilitated passive diffusion: For certain molecules （eg, glucose）, the rate of membrane penetration is greater than expected from their low lipid solubility. One theory is that a carrier component combines reversibly with the substrate molecule at the cell membrane exterior, and the carrier-substrate complex diffuses rapidly across the membrane, releasing the substrate at the interior surface. Carrier-mediated diffusion is characterized by selectivity and saturability: The carrier transports only substrates with a relatively specific molecular configuration, and the process is limited by the availability of carriers. The process does not require energy expenditure, and transport against a concentration gradient does not occur.　　
Active transport: This process is characterized by selectivity and saturability and requires energy expenditure by the cell. Substrates may accumulate intracellularly against a concentration gradient. Active transport appears to be limited to drugs structurally similar to endogenous substances. These drugs are usually absorbed from sites in the small intestine. Active transport processes have been identified for various ions, vitamins, sugars, and amino acids .　
Pinocytosis: Fluid or particles are engulfed by a cell. The cell membrane invaginates, encloses the fluid or particles, then fuses again, forming a vesicle that later detaches and moves to the cell interior. This mechanism also requires energy expenditure. Pinocytosis probably plays a minor role in drug transport, except for protein drugs.　
