Biopharmaceutics

Pharmacokinetics – Distribution Series II – Rate of Drug Distribution

November 13, 2017 Biopharmaceutics, Pharmacokinetics No comments , , , ,

Figure 4.1 shows the plasma concentration and the typical tissue concentration profile after the administration of a drug by intravenous injection. It can be seen that during the distribution phase, the tissue concentration increases as the drug distributes to the tissue. Eventually, a type of equilibrium is reached, and following this, in the postdistribution phase, the tissue concentration falls in parallel with the plasma concentration.

Drug distribution is a two-stage process that consist of:

1.Delivery of the drug to the tissue by the blood

2.Diffusion or uptake of drug from the blood to the tissue

The overall rate of distribution is controlled by the slowest of these steps. The delivery of drug to the tissue is controlled by the specific blood flow to a given tissue. This is expressed as tissue perfusion, the volume of blood delivered per unit time (mL/min) per unit of tissue (g). Once at the tissue site, uptake or distribution from the blood is driven largely by the passive diffusion of drug across the epithelial membrane of the capillaries. Because most capillary membranes are very loose, drugs can usually diffuse from the plasma very easily. Consequently, in most cases, drug distribution is perfusion controlled. The rate of drug distribution will vary from one tissue to another, and generally, drugs will distribute fastest to the tissues that have the higher perfusion rates.

Perfusion-Controlled Drug Distribution

Drug is presented to the tissues in the arterial blood, and any uptake of drug by the tissue will result in a lower concentration of drug leaving the tissue in the venous blood. The amount of drug delivered to the tissue per unit time or rate of presentation of a drug to a tissue is given by

rate of presentation = Q * Ca

where Ca is the drug concentration in the arterial blood and Q is the blood flow to the tissue

rate drug leaves the tissue = Q * Cv

where Cv is the drug concentration in the venous blood

so, rate of up take = Q * (Ca – Cv) (remember the O2ER in oxygen delivery?)

When drug uptake is perfusion controlled, the tissue presents no barrier for drug uptake, and the intial rate of uptake will equal the rate of presentation:

initial rate of uptake = Q * Ca

Thus, it is a first-order process. The value of Ca will change continuously as distribution proceeds throughout the body and as drug is eliminated. When the distribution phase in a tissue is complete, the concentration of drug in the tissue will be in equilibrium with the concentration leaving the tissue (venous blood). The ratio of these concentrations is expressed using the tissue blood partition coefficient (Kp):

where Ct is the tissue concentration. The value of Kp will depend on the binding and the relative affinity of a drug for the blood and tissues. Tissue binding will promote a large value of Kp, whereas extensive binding to the plasma proteins will promote a small Kp.

Once the initial distribution phase is complete, the amount of drug in the tissue (At) at any time is

At = Ct * Vt = Kp * Cv * Vt

Distribution is a first-order process and that the rate of distribution may be expressed using the first-order rate constant for distribution (Kd). The physiological determinants of the rate constant for distribution are most easily identified by considering the redistribution process, which is governed by the same physiological factors and has the same rate constant as those for distribution.

If the drug concentration in arterial blood suddenly became zero; the

rate of redistribution = Kd * At = Kd * (Kp * Cv * Vt) = |Q * (Ca – Cv)| (where Ca = 0) = |Q * –Cv| = Q * Cv

Thus, 

Kd = Q / Vt / Kp, when Ca sudden became zero.

The first-order rate constant for distribution is equal to tissue perfusion divided by the tissue: blood partition coefficient and the corresponding distribution half-life is computed via dividing LN(2) (0.693) by Kd.

Summary

The time it takes for distribution to occur is dependnet on tissue perfusion. Generally, drug distribute to well-perfused tissues such as the lungs and major organs faster than they do to poorly perfused tissues such as resting muscle and skin.

The duration of the distribution phase is also dependent on Kp. If a drug has a high Kp value, it may take a long time to achieve equilibrium even if the tissue perfusion is relatively high. If on the other hand, a drug has a high Kp value in a tissue with low perfusion, it will require an extended period of drug exposure to reach equilibrium.

The amount of drug in tissue at equilibrium depends on Kp and on the size of the tissue. A drug may concentrate in a tissue (high Kp), but if the tissue is physically small, the total amount of drug present in the tissue will be low. The distribution of a drug to such a tissue may not have a strong impact on the plasma concentration of the drug.

Redistribution of a drug from the tissues back to the blood is controlled by exactly the same principles. Thus, redistribution take less time when Kp value is small and the perfusion is high, and will take a long time when the Kp is high and the perfusion is low.

Diffusion-Controlled Drug Distribution

The epithelial junctions in some tissues, such as the brain, placenta, and testes, are very tightly knit, and the diffusion of more polar and/or large drugs may proceed slowly. As a result, drug distribution in these tissues may be diffusion controlled. In this case, drug distribution will proceed more slowly for polar drugs than for more lipophilic drugs. It must be pointed out that not all drug distribution to these sites is diffusion controlled. For example, small lipophilic drugs such as the intravenous anesthetics can easily pass membranes by the transcellular route and display perfusion-controlled distribution to the brain.

Diffusion-controlled distribution may be expressed by Fick's law

rate of uptake = Pm * SAm * (Cpu – Ctu)

where Pm is the permeability of the drug through the membrane (cm/h), SAm the surface area of the membrane (cm2), Cpu the unbound drug concentration in the plasma (mg/mL), and Ctu the unbound concentration in the tissue (mg/mL).

Initially, the drug concentration in the tissue is very low, Cpu >> Ctu, so the equation may be written

rate of uptake = Pm * SAm * Cpu

which can be seen that under these circumstances, the rate of diffusion approximates a first-order process.

Extended-Release Drug Products

July 8, 2016 Biopharmaceutics, Pharmacokinetics No comments , , , , , , , , , ,

Most conventional (immediate release) oral drug products, such as tablets and capsules, are  formulated to release the active drug immediately after oral administration. In the formulation of conventional drug products, no deliberate efforts is made to modify the drug release rate. Immediate-release products generally result in relatively rapid drug absorption and onset of accompanying pharmacodynamic effeccts. In the case of conventional oral products containing prodrug, the pharmacodynamic activity may be slow due to conversion to the active drug by hepatic or intestinal metabolism or by chemical hydrolysis. Alternatively, conventional oral products containing poorly soluble (lipophilic drugs), drug absorption may be gradual due to slow dissolution in or selective absorption across the GI tract, also resulting in a delayed onset time.

PS: 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)

The term modified-releae drug product is used to describe products that alter the timing and/or the rate of release of the drug substance. The pattern of drug release from modified-release (MR) dosage forms is deliberately changed from that of a conventional (immediate-release) dosage formulation to achieve a desired therapeutic objective or better patient compliance. Types of MR drug products include delayed release (e.g., enteric coated), extended release (ER), and orally disintegrating tablets (ODT). The modified-release drug products include:

  • Extended-release drug products. A dosage form that allows at least a twofold reduction in dosage frequency as compared to that drug presented as an immediate-release (conventional) dosage form, including controlled-release, sustained-release, and long-acting drug products.
  • Delayed-release drug products. A dosage form that releases a discrete portion or portions of drug at a time other than promptly after administration. An initial portion may be released promptly after administration. Enteric-coated dosage forms are common delayed-release products.
  • Targeted-release drug products. A dosage form that releases drug at or near the intended physiologic site of action. Targetd-release dosage forms may have either immediate- or extended-release characteristics.
  • Orally disintegrating tablets (ODT). ODT have been developed to disintegrate rapidly in the saliva after oral administration. ODT may be used without the addition of water. The drug is dispersed in saliva and swallowed with little or no water.

The Mission of MR Products

Modified-release drug product should produce a pharmacokinetic profile that provides the desired therapeutic efficacy and minimizes adverse events.

Ideally, the extended-release drug product should release the drug at a constant or zero-order rate. As the drug is released from the drug product, the drug is rapidly absorbed, and the drug absorption rate should follow zero-order kinetics similar to an intravenous drug infusion. The drug product is designed so that the rate of systemic drug absorption is limited by the rate of drug release from the drug delivery system. Unfortunately, most ER drug products that release a drug by zero-order kinetics in vitro do not demonstrate zero-order drug absorption, in vivo. The lack of zero-order drug absorption from these ER drug products after oral administration may be due to a number of unpredictable events happening in the gastrointestinal tract during drug absorption. For factors affecting oral drug absorption please visit the thread "Drug Absorption in Gastrointestinal Tract" at http://www.tomhsiung.com/wordpress/2016/04/drug-absorption-in-the-gastrointestinal-tract/.

Advantages and Disadvantages of Extended-Release Products

ER drug products offer several important advantages over immediate-release dosage forms of the same drug. Extended release allows for sustained therapeutic blood levels of the drug; sustained blood levels provide for a prolonged and consistent clinical response in the patient. Moreover, if the drug input rate is constant, the blood levels should not fluctuate between a maximum and minimum compared to a multiple-dose regimen with an immediate-release drug product. Highly fluctuating blood concentrations of drug may produce unwanted side effects in the patient if the drug level is too high, or may fail to exert the proper therapeutic effect if the drug level is too low. Another advantage of extended release is patient convenience, which leads to better patient compliance. The third advantage is the possible benefit on econmic, that a single dose of an extended-release product may cost less than an equivalent drug dose given several times a day in rapid-release tablets. And the final benefit is that for patients under nursing care, the cost of nursing time required to administer medication is decreased if only one drug dose is given to the patient each day.

There are also a number of disadvantages in using extended-release medication. If the patient suffers from an adverse drug reaction or accidentally becomes intoxicated, the removal of drug from the system is more difficult with an extended-release drug product. Orally administered extended-release drug products may yield erratic or variable drug absorption as a result of various drug interactions with the contents of the GI tract and changes in GI motility. The formulation of extended-release drug products may not be practical for drugs that are usually given in large doses (e.g., 500 mg) in conventional dosage forms. Because the extended-release drug product may contain two or more times the dose given at more frequent intervals, the size of the extended-release drug product may have to be quite large, too large for the patient to swallow easily.

The extended-release dosage form contains the equivalent of two or more drug doses given in a conventional dosage form. Therefore, failure of the extended-release dosage form may lead to dose dumping. Dosing dumping is defined either as the release of more than the intended fraction of drug or as the release of drug at a greater rate than the customary amount of drug per dosage interval, such that potentially adverse plasma levels may be reached.

Kinetics of Extended-Release Dosage Form

The amount of drug required in an extended-release dosage form to provide a sustained drug level in the body is determined by the pharmacokinetics of the drug, the desired therapeutic level of the drug, and the intended duration of action. In general, the total dose required (Dtot) is the sum of the maintenance dose (Dm) and the initial dose (DI) released immediately to provide a therapeutic blood level.

Dtot = DI + Dm (Equation 17.1)

In practice, Dm (mg) is released over a period of time and is equal to the product of td (the duration of drug release) and the zero-order rate kr0td (mg/h). Therefore, Equation 17.1 can be expressed as

Dtot = DI + kr0td (Equation 17.2)

Ideally, the maintenance dose (Dm) is released after DI has produced a blood level equal to the therapeutic drug level (Cp). However, due to the limits of formulations, Dm actually starts to release at t = 0. Therefore, D1 may be reduced from the calculated amount to avoid "topping."

Dtot = DI – kr0tp + kr0td (Equation 17.3)

Equation 17.3 describes the total dose of drug needed, with tp representing the time needed to reach peak drug concentration after the initial dose.

For a drug that follows a one-compartment open model, the rate of elimination (R) needed to maintain the drug at a therapeutic level (Cp) is

R = CpClT (Equation 17.5)

where ClT is the clearance of the drug and kr0 must be equal to R (kr0 = R) in order to provide a stable blood level of the drug. So if we substitute R for kr0 we get the follow expression:

Dtot = DI + CpClT*tau (Equation 17.6)

For many sustained-release drug products, there is no built-in loading dose (i.e., DI = 0). The dose needed to maintain a therapeutic concentration for tau hours is

D0 = CpClT*tau (Equation 17.6)

(The End)

Drug Absorption in the Gastrointestinal Tract

April 7, 2016 Biopharmaceutics, Pharmacokinetics No comments , , , , , , , , , , , ,

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)

Passive Diffusion

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(CGICP) ≈ 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)
  • pH
  • Fluid volume in the lumen
  • Enzymes
  • 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
  • Coabsorption factors
  • Bile
  • villi and microvilli
  • GI perfusion/blood flow and lymph circulation
  • Microorganism/stability
  • First pass effect/prodrug
  • Hepatoenteral circulation
  • 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.

Gastrointestinal motility

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.

Intestinal Motility

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