Which of the following does not affect the rate of diffusion through a membrane?

Regardless of the absorption site, the drug must cross the cell membrane to reach the systemic circulation. This can occur primarily in one of two ways, either through passive (simple) diffusion or carrier-mediated membrane transporters. 

The most common mechanism of absorption for drugs is passive diffusion. This process can be explained through the Fick law of diffusion, in which the drug molecule moves according to the concentration gradient from a higher drug concentration to a lower concentration until equilibrium is reached. Passive diffusion can occur in an aqueous or lipid environment. Aqueous diffusion occurs in the aqueous compartment of the body, such as interstitial space or through aqueous pores in the endothelium of blood vessels. Drugs that are bound to albumin or other large plasma proteins cannot permeate most aqueous pores. On the other hand, lipid diffusion occurs through the lipid compartment of the body. Therefore it is considered the most important factor for drug permeability due to the greater number of lipid barriers that separate the compartments of the body. The lipid-aqueous partition coefficient of the drug can be used to determine how rapidly the drug moves between lipid and aqueous mediums. 

Another mechanism of absorption is via carrier-mediated membrane transporters. Numerous specialized carrier-mediated membrane transport systems are present in the body to transport ions and nutrients, particularly in the intestine. Such systems include active and facilitated diffusion. Active diffusion is an energy-consuming system essential for GI absorption; and renal and biliary excretion of many drugs. This process facilitates the absorption of some lipid insoluble drugs, which mimics natural physiological metabolites such as 5-fluorouracil from the GI tract. In contrast to passive diffusion, active diffusion enables the movement of drugs from regions with low drug concentrations to regions with higher drug concentrations.

With active diffusion, the carrier binds to form a complex with the drug. This complex facilitates the transportation of the drug across the membrane and then disassociates on the other side. The carrier molecule may be highly specific to the drug molecule. Drugs sharing similar structures can compete with each other for the carrier in absorption sites. Since there are only a small number of carrier molecules available, the binding sites on the carrier may become saturated if the drug concentration is very high, after which the dose increases do not affect the concentration of the drug. While some transporters facilitate absorption, other transporters such as P-glycoprotein (P-gp) can effectively impede drug absorption. P-gp (also known as MDR1) is an energy-dependent efflux transporter that facilitates the secretion of molecules back into the intestinal lumen, thereby restricting overall absorption. Facilitated diffusion is another transporter system that appears to play a minor role in terms of drug absorption. It is similar to the active diffusion system in that both are saturable and exhibit drug selectivity and competition kinetics. However, the main differences are that facilitated diffusion does not require energy, and unlike active transport, does not enable the movement against a concentration gradient. An example of a facilitated diffusion system is the organic cation transporter 1 (OCT1), which facilitates the movement of some drugs such as metformin, an antidiabetic agent.

Drug-specific factors that affect drug absorption include the physicochemical and pharmaceutical variables of drugs. One example of the physicochemical variables is the drug solubility and the effect of pH and pKa, where most drugs act as weak acids or bases in solutions in both ionized and non-ionized forms. The ionized drugs are hydrophilic and cannot cross the membrane of the cell. Whereas the non-ionized drugs appear to be lipophilic and can penetrate the cell membrane easily by simple diffusion. The distribution of weak electrolytes across membranes would result from the pH gradient across the membrane and the drug's pKa. Weakly acidic drugs are easily absorbed in a low pH medium such as in the stomach. Whereas weakly basic drugs are not absorbed until they reach the higher pH medium in the small intestine. 

Other physicochemical variables such as particle size and surface area, dissolution rate, amorphism, polymorphism characteristics, and nature of the dosage form will also affect systemic drug absorption. The rate of dissolution is the amount of the solid substance that turns into a solution per time at standard conditions of pH, solvent composition, and temperature, with a constant surface area. For example, cisapride, a gastroprokinetic agent, has a low aqueous solubility. However, it has good oral bioavailability due to its rapid rate of dissolution in GI fluids. The particle size is inversely related to the dissolution rate. Thus, reducing particle size increases surface area and, consequently, a higher dissolution rate. Micronizing the drug particles increases the dissolution rate and solubility. For example, digoxin is found to have 100% bioavailability in the micronized tablet. Furthermore, the internal structure of the drug can be either in a crystalline or amorphous form.

Polymorph is a term in which the solid substance has more than one crystalline form. The polymorphs can vary in their physical properties, such as solubility, hardness, and melting point. For example, chloramphenicol palmitate has three polymorphic forms A, B, & C. Among all these, form B is found to have the highest absorption and bioavailability. Pharmaceutical variables include the presence of different excipients (inactive ingredients), which may increase or decrease the absorption rate depending on the added ingredient. There are several dosage forms in which the drug can be administered. Each dosage form has a different absorption rate depending on many factors, including the nature of the dosage form and the site of administration. Generally, for orally administered dosage forms, solutions have a higher rate of absorption. Other pharmaceutical variables include drug expiration and storage condition.

Patient-specific factors affecting the drug absorption (physiological variables) include age, gastric emptying time, intestinal transit time, disease status, blood flow at the absorption site, pre-systemic metabolism, and GI content.  With increased age, many physiological changes occur, which may lead to decreased drug absorption. Critically ill patients may have reduced blood flow to the GI tract, which will result in reduced drug absorption. Generally, intestinal absorption is more critical for most drugs than any other site in the GI tract due to the increased surface area of the intestinal mucosa. The duodenal mucosa has the quickest drug absorption because of such anatomical characteristics as villi and microvilli, which provide a large surface area. However, these villi are much less abundant in other parts of the GI tract. Drugs may be absorbed from the GI tract at a different rate. Before orally administered drugs reach the circulation, they can be metabolized within the gut wall or the liver. This is known as first-pass metabolism, which will result in a decreased amount of active drug absorbed. Food content appears to affect the absorption rate of many orally administered drugs. For example, the absorption rate of levodopa, an antiparkinsonian drug, is decreased when administered with protein-containing food. While the absorption of albendazole, an antiprotozoal agent, is enhanced with lipid-containing food.

What does not affect the rate of diffusion through a membrane?

What does not affect diffusion in the cell?

Which one of the following does not increase the rate of diffusion?

What does not affect the rate of facilitated diffusion?