关于药物知识医学英语阅读
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药物知识医学英语阅读：药物吸收
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.
必备医学知识阅读：药物生物利用度
The physicochemical properties of a drug govern its absorptive potential, but the properties of the dosage form (which partly depend on its design and manufacture) can largely determine drug bioavailability. Differences in bioavailability among formulations of a given drug can have clinical significance. Thus, the concept of equivalence among drug products is important in making clinical decisions. Chemical equivalence refers to drug products that contain the same compound in the same amount and that meet current official standards; however, inactive ingredients in drug products may differ. Bioequivalence refers to chemical equivalents that, when administered to the same person in the same dosage regimen, result in equivalent concentrations of drug in blood and tissues. Therapeutic equivalence refers to drug products that, when administered to the same person in the same dosage regimen, provide essentially the same therapeutic effect or toxicity. Bioequivalent products are expected to be therapeutically equivalent.
Sometimes therapeutic equivalence may be achieved despite differences in bioavailability. For example, the therapeutic index (ratio of the maximum tolerated dose to the minimum effective dose) of penicillin is so wide that moderate blood concentration differences due to bioavailability differences in penicillin products may not affect therapeutic efficacy or safety. In contrast, bioavailability differences are important for a drug with a relatively narrow therapeutic index.
The physiologic characteristics and comorbidities of the patient also affect bioavailability.
Absorption rate is important because even when a drug is absorbed completely, it may be absorbed too slowly to produce a therapeutic blood level quickly enough or so rapidly that toxicity results from high drug concentrations after each dose.
Causes of Low Bioavailability
When a drug rapidly dissolves and readily crosses membranes, absorption tends to be complete, but absorption of orally administered drugs is not always complete. Before reaching the vena cava, a drug must move down the GI tract and pass through the gut wall and liver, common sites of drug metabolism; thus, a drug may be metabolized (first-pass metabolism) before it can be measured in the systemic circulation. Many drugs have low oral bioavailability because of extensive first-pass metabolism. For such drugs (eg, isoproterenol, norepinephrine, testosterone), extraction in these tissues is so extensive that bioavailability is virtually zero. For drugs with an active metabolite, the therapeutic consequence of first-pass metabolism depends on the contributions of the drug and the metabolite to the desired and undesired effects.
Low bioavailability is most common with oral dosage forms of poorly water-soluble, slowly absorbed drugs. More factors can affect bioavailability when absorption is slow or incomplete than when it is rapid and complete, so slow or incomplete absorption often leads to variable therapeutic responses.
Insufficient time in the GI tract is a common cause of low bioavailability. Ingested drug is exposed to the entire GI tract for no more than 1 to 2 days and to the small intestine for only 2 to 4 h. If the drug does not dissolve readily or cannot penetrate the epithelial membrane (eg, if it is highly ionized and polar), time at the absorption site may be insufficient. In such cases, bioavailability tends to be highly variable as well as low. Age, sex, activity, genetic phenotype, stress, disease (eg, achlorhydria, malabsorption syndromes), or previous GI surgery can affect drug bioavailability.
Reactions that compete with absorption can reduce bioavailability. They include complex formation (eg, between tetracycline and polyvalent metal ions), hydrolysis by gastric acid or digestive enzymes (eg, penicillin and chloramphenicol palmitate hydrolysis), conjugation in the gut wall (eg, sulfoconjugation of isoproterenol), adsorption to other drugs (eg, digoxin and cholestyramine), and metabolism by luminal microflora.
Assessment of Bioavailability
Assessment of bioavailability from plasma concentration-time data usually involves determining the maximum (peak) plasma drug concentration, the time at which maximum plasma drug concentration occurs (peak time), and the area under the plasma concentration-time curve. The plasma drug concentration increases with the extent of absorption; the peak is reached when the drug elimination rate equals absorption rate. Bioavailability determinations based on the peak plasma concentration can be misleading, because drug elimination begins as soon as the drug enters the bloodstream. The most widely used general index of absorption rate is peak time; the slower the absorption, the later the peak time. However, peak time is often not a good statistical measure because it is a discrete value that depends on frequency of blood sampling and, in the case of relatively flat concentrations near the peak, on assay reproducibility.
AUC is the most reliable measure of bioavailability. It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation. For an accurate measurement, blood must be sampled frequently over a long enough time to observe virtually complete drug elimination. Drug products may be considered bioequivalent in extent and rate of absorption if their plasma-level curves are essentially superimposable. Drug products that have similar AUCs but differently shaped plasma-level curves are equivalent in extent but differ in their absorption rate-time profiles.
Single vs. multiple doses: Bioavailability may be assessed after single or repetitive (multiple) dosing. More information about rate of absorption is available after a single dose than after multiple dosing. However, multiple dosing more closely represents the usual clinical situation, and plasma concentrations are usually higher than those after a single dose, facilitating data analysis. After multiple dosing at a fixed-dosing interval for four or five elimination half-lives, the blood drug concentration should be at steady state (the amount absorbed equals the amount eliminated within each dosing interval). The extent of absorption can then be analyzed by measuring the AUC during a dosing interval. Measuring the AUC over 24 h is probably preferable because of circadian variations in physiologic functions and because of possible variations in dosing intervals and absorption rates during a day.
For drugs excreted primarily unchanged in urine, bioavailability can be estimated by measuring the total amount of drug excreted after a single dose. Ideally, urine is collected over a period of 7 to 10 elimination half-lives for complete urinary recovery of the absorbed drug. Bioavailability may also be assessed after multiple dosing by measuring unchanged drug recovered from urine over 24 h under steady-state conditions.
