Where are oral drugs most commonly absorbed?

Absorption of Drugs in the Neonate

Drug absorption is the passage of a drug from its site of administration into the circulation. In neonates who can tolerate gastric feedings, the oral route of drug administration is the most common because of its convenience and safety. The absorption of a drug or substance through the gastrointestinal system may be defined as the net movement of a drug from the gastrointestinal lumen into the systemic circulation draining this organ. This process entails the movement of drugs across the gastrointestinal epithelium, which behaves like a semipermeable lipid membrane and constitutes the main barrier to absorption. The various processes operating to induce the transepithelial membrane movement of drug molecules include simple diffusion through lipid membranes or aqueous pores of the membrane; filtration through aqueous channels or membrane pores; carrier-mediated transport, such as active transport or facilitated diffusion; and vesicular transport, such as pinocytosis. Of these, the most important is the process of simple diffusion, because most drugs administered orally are absorbed through this process.

The rate and extent of gastrointestinal drug absorption are partly determined by the physical and chemical characteristics of the drug. Polarity, nonlipid solubility, and a large molecular size tend to decrease absorption. In contrast, nonpolarity, lipid solubility, and a small molecular size increase absorption. The degree of ionization, determined by the pKa of the drug and the pH of the solution in which it exists, is an important determinant in drug absorption. The gastrointestinal epithelium is more permeable to the nonionized form, because this portion is usually lipid soluble and favors absorption. The degree of drug ionization changes as the pH increases from the stomach through the distal portion of the gut.

Ionization also changes with the substantial changes in gastric pH observed during the neonatal period. Gastric acid production is generally low at birth, and the gastric pH is usually 6-8. In the first few hours of life, a burst of acid secretion occurs, decreasing the pH to values of 1-3. Acid secretion then returns to a low level, and the gastric pH remains near neutral for the first 10 days of life.27 The gastric pH then tends to fall and approaches adult values by 2 years of age. These initial fluctuations in gastric acid secretion do not appear to occur in premature neonates, because their gastric pH remains near 6-8 for the first 14 days of life.3 Clinically, the result of any decrease in pH is the increased absorption of weak acids (e.g., furosemide, phenobarbital), because they are more likely to be in the un-ionized, lipid-soluble state. Conversely, an increase in pH enhances the absorption of weak bases (e.g., morphine, erythromycin) and limits the absorption of weak acids.

The slow gastric emptying time and intestinal motility in the newborn may also affect drug absorption. The primary site for drug absorption is the proximal bowel, which has the greatest absorptive surface area. With slower motility and emptying, it takes longer for a drug to reach this site of absorption, and the rate at which absorption can occur may be limited. Conversely, a slow transit time or slow intestinal motility may facilitate the absorption of some drugs, such as iron, which is primarily absorbed in the duodenum.

12.7.2.2 Zero-order drug absorption

Zero-order drug absorption can also occur with oral drug absorption by a saturable process or a controlled release drug delivery system. Following oral drug administration, by zero-order drug absorption, drug in the GI is absorbed systemically at a constant rate of Kao. The rate of drug input is simply Kao:

(12.13)dDGI dt=Kao

where Kao is the rate of drug absorption, which is a constant. In this case, the time for complete drug absorption to occur is equal to Dose of the drug/Kao.

Drug Absorption and Route of Drug Administration

Absorption specifically refers to the process of drug transfer from its site of administration to the bloodstream (seeFig. 45.2). Drugs typically enter the body via intravenous (IV), enteral (per oral, PO), intramuscular, intrapulmonary, subcutaneous, or percutaneous routes and are then absorbed into the circulation as free drug. The route of administration affects the concentration of the drug over time (seeFig. 45.3). Bioavailability of a drug refers to the fraction of the administered dose that reaches the circulation but does not consider the rate of drug absorption. Bioavailability is determined by comparing the respective area under the plasma concentration curves (AUC) after a non-IV form of administration with the AUC after an IV administration. IV administration of a drug provides the most consistent, reliable absorption into the circulation and, therefore, defines a bioavailability of 100%.

For enteral medications, the bioavailability depends on biochemical properties of the drug, the formulation, and patient-specific factors such as gastric acidity, gastric emptying time, and intestinal absorption and transit time. Bioavailability is reduced by incomplete absorption and by first-pass metabolism as the drug enters the portal circulation where it can be metabolized in the liver before reaching the systemic circulation. Drugs administered enterally enter the circulation more slowly than IV bolus-administered drugs and therefore achieve a lower maximum drug concentration (Cmax) later after administration (seeFig. 45.3). Drug-specific dose adjustment is needed when converting IV to enteral formulations to achieve consistent exposure.

Neonates have unique absorption properties that impact drug concentrations after enteral administration.1,6,14,20 Reduced gastric acidity can increase absorption of acid-labile molecules (penicillin) and decrease absorption of weak organic acids (phenytoin, phenobarbital). Slower gastric emptying time and intestinal motility can change the time to absorb the drug and amount of drug absorbed. Enteral absorption often improves as infants become older. Absorption of enteral medications is often decreased in infants with GI pathology or changes in perfusion to the GI system. Anticipating differences in bioavailability helps guide dose adjustment when converting between IV and PO route of administration.

Bioavailability after intramuscular (IM) and percutaneous (topical) administration can be affected by tissue mass, perfusion, drug permeability, and surface area. In neonates, reduced muscle perfusion and contractility can limit absorption after IM administration.1,14 When drugs are applied topically, the percutaneous absorption of the drug is directly related to the degree of skin hydration and relative surface area and inversely related to the thickness of the stratum corneum. Percutaneous application of medications in premature infants can lead to large systemic drug exposures given their larger surface area and thin stratum corneum.

Absorption and distribution

Drug absorption across the gut wall is not greatly affected by ageing, although bioavailability may be increased due to reduced first-pass metabolism. Older people tend to have a lower lean body mass and a relative increase in body fat compared with young adults. The apparent volume of distribution (Vd) of water-soluble drugs such as digoxin may therefore be lower in the elderly, and a smaller loading dose would be needed. Conversely, lipid-soluble drugs may be eliminated more slowly because of their increased Vd resulting from increased body fat.

Extravascular Drug Absorption

Intravenous (IV) drug administration is assumed to be the most dependable and accurate route for drug delivery, with a bioavailability of 100%. Absorption of drugs from tissues and organs (e.g., intramuscular, transdermal, rectal) can also be affected by development (Table 73.2). Intramuscular (IM) blood flow changes with age, which can result in variable and unpredictable absorption. Reduced muscular blood flow in the 1st few days of life, the relative inefficiency of muscular contractions (useful in dispersing an IM drug dose), and an increased percentage of water per unit of muscle mass may delay the rate and extent of drugs given intramuscularly to the neonate. Muscular blood flow increases into infancy, and thus the bioavailability of drugs given by the IM route is comparable to that seen in children and adolescents.

In contrast,mucosal permeability (rectal and buccal) in the neonate is increased and thus may result in enhanced absorption by this route.Transdermal drug absorption in the neonate and very young infant is increased because of the thinner and more hydrated stratum corneum (Fig. 73.3E). In addition, the ratio of body surface area to body weight is greater in infants and children than in adults. Collectively, these developmental differences may predispose the child to increased exposure and risk for toxicity for drugs or chemicals placed on the skin (e.g., silver sulfadiazine, topical corticosteroids, benzocaine, diphenhydramine), with higher likelihood of occurrence during the 1st 8-12 mo of life.

Normal developmental differences in drug absorption from most all extravascular routes of administration can influence the dose–plasma concentration relationship in a manner sufficient to alter pharmacodynamics. The presence of disease states that influence a physiologic barrier for drug absorption or the time that a drug spends at a given site of absorption can further influence drug bioavailability and effect.

b. Permeability in the GI Tract

Permeability is the ability of a molecule to be transported through the GI barrier. Understanding the in vitro permeability of a drug allows the prediction of oral absorption and hence its bioavailability.

A drug is absorbed through diffusion across a series of separate barriers where the single layer of epithelial cells is the most significant barrier to absorption. Many in vitro methods have been developed for the study of this phenomenon. These methods include small animal gut studies, cell culture (i.e., Caco-2 cell culture model), octanol–water partition coefficients, measures of hydrogen bonding and desolvation energies, immobilized artificial membranes, and retention time on reversed-phase HPLC columns.

Among these testing methods, the small animal GI model and the Caco-2 cell culture model have shown the best correlation with oral absorption in vivo. The Caco-2 culture system consists of a monolayer of human intestinal epithelial cells grown on semipermeable supports such as polycarbonate membranes. Because the cells are human in origin, they exhibit many characteristics of the human small intestinal epithelium.32 The permeability coefficients relative to the extents of human drug absorption33 are listed here:

This system is widely used in the pharmaceutical industry as an effective model for predicting drug absorption. Other advantages include

•

Potential for automation, thus, high throughput robotic operation conducted with cost effectiveness and shortened development time

Minimal use of animals for experimentation, currently a sensitive issue of society

Small amounts of drug substance used for multiple testing with the drug substance supply restricted during the earlier discovery stage; processes based on micro technique

Potential screening method development for testing oral dosage form selection

7.2.10 Nasal Absorption of Insulin

Nasal absorption of insulin has been of interest since 1983 (Moses et al., 1983). More recent clinical studies tested its long-term acceptability and efficacy in Type-I diabetic patients (Fraumann et al., 1987) and assessed the kinetics of intranasal insulin with a medium-chain phospholipid (Drejer et al., 1990). Nasal irritation was only slight and proportional to the insulin dosage. Compared with subcutaneous injection, intranasal insulin has a quicker onset of action and a much more uniform time course of absorption. Bioavailability was 8–11% and 24% in the meal-relevant period. Further studies, however, are needed before widespread clinical use can be recommended.

ABSORPTION

Drug absorption differences in the neonate enhance neonates' susceptibility to toxicity. The neonate has a higher gastric pH due to decreased gastric acid secretion. Since gastrointestinal absorption of many drugs is pH dependent, the continuous changes that occur in gastric pH from birth through the second year of life complicate predictions of drug absorption.7,8 In addition, the more alkaline gastric environment of infants coupled with their lack of mature mucosal immunologic defenses allows growth of Clostridium botulinum and makes them susceptible to botulism (see Chapter 26). As compared with older patient groups, gastric emptying is slower in the neonate and infant. Thus, absorption of drugs may be delayed considerably, leading to a delay in the time to peak serum concentration and a decrease in peak serum concentration. If these factors are not taken into account when initially dosing medications in the neonate, supplemental dosing may be necessary with the consequent increase in potential toxicity.

Absorption of drugs administered by the intramuscular route is also altered in the neonate. Since the relative blood flow of the various muscle groups changes dramatically, particularly in the first 2 weeks of postnatal life, and muscle activity may also undergo alterations, intramuscular administration of medications may produce inconsistent and unreliable absorption in both premature and full-term infants.7–9

Transdermal absorption of drugs may also lead to toxicity in the neonate. The comparatively reduced thickness of the stratum corneum, particularly in the premature infant, permits more effective absorption by the cutaneous route.8,9 Indeed, the literature contains several reports of toxicity in neonates resulting from percutaneous absorption (see Dermatologic Exposures below).10–13

9.3.6.1.2 Factors Affecting Pulmonary Deposition

Drug absorption from pulmonary epithelia occurs only after inhaled drug deposits in the lung and undeposited aerosolized particles clear out of the lung in expired air. Depending upon the type of inhalation technology, only about 20–50% of the pulmonary-delivered dose is deposited in the peripheral lung. The particle size of inhaled substances will affect the absorption of the inhaled drug to systemic circulation. Particles >8 μm in aerodynamic diameter deposit in the central and conducting airways by inertial impaction, whereas fine particles, those <3 μm in diameter, deposit primarily in the respiratory regions of the peripheral lung by diffusion. Particles between 3 and 8 μm in diameter largely deposit in the transitional zones of the lung by sedimentation. The particles that deposit in the upper and central airways are rarely absorbed systemically, as these are efficiently and rapidly removed by mucociliary clearance.