Info

a Based on data in Ref. 14. b Based on data in Ref. 15. c Based on data in Ref. 27.

a Based on data in Ref. 14. b Based on data in Ref. 15. c Based on data in Ref. 27.

absorption rate constant. Some cautions must be taken in the application of this method. Although the overall absorption process in humans for many drugs appears consistent with the characteristics of a first-order kinetic process, there are some questions regarding which of the sequential steps in the absorption process is rate-limiting. As discussed in a thorough review of mass transport phenomena (32), the Ko/w of a solute will govern its movement across a lipid-like membrane as long as the membrane is the predominant barrier to diffusion. However, for such membranes, when the Ko/w becomes very large, the barrier controlling diffusion may no longer be the membrane but rather an aqueous diffusion layer surrounding the membrane. Thus, for some molecules, depending on their physicochemical characteristics, the rate-limiting step in membrane transport will be movement through or out of the membrane, while for other compounds the rate-limiting step will be diffusion through an aqueous layer. Our incomplete understanding of drug transport across biological membranes is not that surprising, given the complexity of the system and the experimental requirements needed to make unequivocal statements about this process on a molecular level.

The analysis of absorption data in humans includes traditional modeling and data-fitting techniques as well as so-called moment analysis, in addition to a process referred to as deconvolution (33). Absorption processes are now often characterized by a mean

Figure 9 Schematic representation depicting the movement of drug molecules from the absorbing (mucosal or apical) surface of the GIT to the basolateral membrane and from there to blood. (Left) Passive, non-energy-dependent processes of transcellular movement through the epithelial cell and paracellular transport via movement between epithelial cells. (Right) Specialized carrier-mediated (influx) transport into the epithelial cell and carrier-mediated efflux transport of drug out of the epithelial cell. Source: Courtesy of Saguaro Press.

Figure 9 Schematic representation depicting the movement of drug molecules from the absorbing (mucosal or apical) surface of the GIT to the basolateral membrane and from there to blood. (Left) Passive, non-energy-dependent processes of transcellular movement through the epithelial cell and paracellular transport via movement between epithelial cells. (Right) Specialized carrier-mediated (influx) transport into the epithelial cell and carrier-mediated efflux transport of drug out of the epithelial cell. Source: Courtesy of Saguaro Press.

absorption (or input) time (i.e., the average amount of time that the drug molecules spend at the absorption site) or by a process called deconvolution. The former analyses result in a single value (such as absorption half-life or mean absorption time) and the latter analysis results in a profile of the absorption process as a function of time (e.g., absorption rate or cumulative amount absorbed vs. time). These approaches offer alternative ways of interpreting the absorption process.

Most drugs appear to be absorbed in humans by passive diffusion (linear or first-order kinetics) over the therapeutic dose range. The predominant pathway taken by most drugs is through the epithelial cell, the transcellular route. It is this route that requires the compound to have a reasonable Ko/w (greater than 1 and less than about 105). This route is indicated in Figure 9 as the arrow moving through the cell from the mucosal (or apical) absorbing surface to the basolateral membrane. In contrast, small polar molecules (Ko/w < 1) may have access to a convoluted route that exists between adjacent epithelial cells. This pathway has a tight junction at the apical surface as well as other junctions along the pathway (apical junction complex). This route is referred to as being paracellular (Fig. 9). The molecular size cutoff for this route is about 500 Da (34). It remains unclear the extent to which this pathway may be practically affected to increase absorption by so-called tight junction modulators (35).

Since many essential nutrients (e.g., monosaccharides, amino acids, and vitamins) are water soluble, they have low Ko/ws, which should result in poor absorption from the GIT. However, to ensure adequate uptake of these materials from food, the intestine has developed specialized absorption mechanisms that depend on membrane participation (energy expenditure) and require the compound to have a specific chemical structure. This uptake carrier transport mechanism is illustrated in Figure 9. Absorption by a specialized carrier mechanism has been shown to exist for several agents used in cancer chemotherapy (5-fluorouracil and 5-bromouracil) (36), which may be considered "false" nutrients in that their chemical structures are very similar to essential nutrients for which the intestine has a specialized transport mechanism. These specialized mechanisms are generally found in only a limited section of the small intestine that is sometimes referred to as an "absorption window."

It would be instructive to examine some studies concerned with riboflavin and ascorbic acid absorption in humans, as these illustrate how one may treat urine data to

Figure 10 Urinary excretion of riboflavin (A,B) and ascorbic acid (C,D) in humans as a function of oral dose. Graphs A and C illustrate the nonlinear dependence of absorption on dose, which is suggestive of a saturable specialized absorption process. Graphs B and D represent an alternative graph of the same data and illustrate the reduced absorption efficiency as the dose increases. Source: Graphs A and C based on the data in Ref. 37 and graphs B and D based on the data in Ref. 38.

Figure 10 Urinary excretion of riboflavin (A,B) and ascorbic acid (C,D) in humans as a function of oral dose. Graphs A and C illustrate the nonlinear dependence of absorption on dose, which is suggestive of a saturable specialized absorption process. Graphs B and D represent an alternative graph of the same data and illustrate the reduced absorption efficiency as the dose increases. Source: Graphs A and C based on the data in Ref. 37 and graphs B and D based on the data in Ref. 38.

explore the mechanism of absorption. If a compound is absorbed by a passive mechanism, a plot of amount absorbed (or amount recovered in the urine) versus dose ingested will provide a straight-line relationship. In contrast, a plot of percentage of dose absorbed (or percentage of dose recovered in the urine) versus dose ingested will provide a line of slope zero (i.e., a constant fraction of the dose is absorbed at all doses). If the absorption process requires membrane involvement, the absorption process may be saturated as the oral dose increases, making the process less efficient at larger doses (i.e., there are more drug molecules than sites on the transporter). As a result, a plot of amount absorbed versus dose ingested will be linear at low doses, curvilinear at larger doses, and approach an asymptotic value at even larger doses. One sees this type of relationship for riboflavin and ascorbic acid in Figure 10A and C, suggesting nonpassive absorption mechanisms in humans (37,38). This nonlinear relationship is reminiscent of Michaelis—Menten saturable enzyme kinetics from which one may estimate the kinetic parameters (Km and Vmax) associated with the absorption of these vitamins. Figure 10B and D illustrates an alternative plot, percentage absorbed versus dose ingested. For a nonpassive absorption process, the percentage dose absorbed will decrease as the dose increases as a result of saturation of the transport mechanism, resulting in a reduction in absorption efficiency. It has been suggested (38) that one means of overcoming the decrease in absorption efficiency is to administer small divided doses rather than large single doses, as illustrated later for ascorbic acid.

L-Dopa absorption may be impaired if the drug is ingested with meals containing proteins (39). Amino acids formed from the digestion of protein meals, which are absorbed by a specialized mechanism, may competitively inhibit L-dopa absorption if the drug is also transported by the same transport carrier. There is evidence (in animals) indicating a specialized absorption mechanism for phenylalanine and L-dopa, and there are data illustrating L-dopa inhibition of phenylalanine and tyrosine absorption in humans (40,41). L-Dopa appears to be absorbed by the same specialized transport mechanism responsible for the absorption of other amino acids (42). In a latter section, several of the complicating factors in L-dopa absorption that influence therapy are discussed.

In addition to some anticancer agents being absorbed by a specialized process in humans (e.g., methotrexate) (43), there is evidence to suggest that a similar mechanism exists for the absorption of aminopenicillins (e.g., amoxicillin) (44) and amino-cephalosporins (e.g., cefixime) (45). Absorption of these compounds appears to be linked to cellular amino acid or peptide transporters. Other compounds that have the requisite structural properties may also benefit from those transporting systems (e.g., gabapentin) (46). This behavior may represent an important observation for the new generation of drugs being developed through the application of biotechnology (e.g., peptides), assuming such compounds are sufficiently stable in the GIT. Calcium channel blockers, such as nifedipine, have been shown to increase the absorption of amoxicillin and cefixime (44,45). This may result from the role of calcium in the transport process, the inhibition of which (i.e., calcium channel blockers) enhances absorption.

In direct contrast with specialized uptake transport of a drug into the epithelial cell, is a process referred to as "efflux transport," the facilitated movement of a drug out of the cell. This phenomenon explains the resistance of cancerous cells to some chemo-therapeutic agents (47). It is now apparent that this mechanism exists in epithelial cells of numerous organ systems, including the GIT, liver, lung, kidney, and brain (48). There is a cell surface glycoprotein (P-glycoprotein, P-gp), a multidrug-resistance protein (MDR), which is responsible for the efflux mechanism. This protein belongs to a large family of glycosylated membrane proteins referred to as ATP-binding cassette (ABC) transporters. As depicted in Figure 9, the cell surface glycoprotein will attach to the drug molecule and escort it out of the cell and back into the gut lumen, hence the term, efflux transporter. The presence of this protein in the GIT has significant implications for drug absorption, bioavailability, and drug-drug (and drug-nutrient) interactions (49-54). Substrates for this transporter have a diverse range of structures and include compounds such as (49) anticancer agents (e.g., anthracyclines, taxol, and vinblastine), cardioactive drugs (e.g., digoxin, phenytoin, quinidine, and verapamil), immunosuppressants (e.g., cyclosporine and tacrolimus), erythromycin, and quinine. The P-gp may be inhibited or induced and the efflux transport process may be saturated. The former is the basis for many potential drug-drug and nutrient-drug interactions and the latter limits the efficacy of the transporter.

It is difficult to unequivocally implicate P-gp as the mechanism of an interaction resulting in altered absorption since the absorbing intestinal cells are rich in metabolizing enzymes, especially those responsible for phase I oxidative metabolism, the cytochrome P450 family (CYP450). Within that family the most significant isozyme is CYP3A4, since it is less selective of substrates (a "promiscuous" enzyme), and as a result, it accounts for about 50% of all drug-drug and nutrient-drug interactions. Both P-gp and CYP3A4 are present in the same locations and appear to share the same substrates. As a consequence, it is difficult to unequivocally ascribe alterations in absorption to be the exclusive result of either the efflux transporter or the enzyme. This is the case, for example, for cyclosporine whose absorption is enhanced in the presence of several drugs (e.g., ketoconazole), which may be due to inhibition of P-gp efflux or inhibition of CYP3A4 metabolic activity or both (55). A further complication is the need to consider the systemic effect of altered P-gp activity on drug clearance, an effect that is independent of the absorption process.

Efflux transport and gut wall metabolism tend to decrease systemic drug exposure and thereby reduce systemic bioavailability. It appears that the efflux transporter may act in concert with metabolizing enzymes in the enterocytes by limiting exposure of the enzyme to drug by "pumping" the drug out of the enterocyte and back into the gut. This action reduces the potential for enzyme saturation, which, in turn, minimizes drug from "swamping" the enzyme and being systemically absorbed. These mechanisms are consistent with the protective barrier function of the GIT.

The significance of P-gp in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in "knockout" mice that do not have intestinal P-gp. The gene responsible for producing that protein has been "knocked out" of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) following oral dosing of the anticancer drug, paclitaxel (Taxol), compared with the control animals (56). Another line of evidence is the recent report of an interaction between the p-adrenergic blocking agents, talinolol and digoxin (57). Talinolol coadministration resulted in a significant increase in digoxin plasma concentrations (and AUC), and since talinolol and digoxin are not substrates for CYP3A3, the effect on absorption may be attributed to inhibition of P-gp, which modulates digoxin absorption.

PHYSIOLOGICAL FACTORS GOVERNING DRUG ABSORPTION Components and Properties of Gastrointestinal Fluids

The characteristics of aqueous GI fluids to which a drug product is exposed will exert an important influence on what happens to that dosage form in the tract and on the pattern of drug absorption. To appreciate clearly how physiological factors influence drug absorption, one must consider the influence of these variables on the dosage form per se, that is, how these variables influence drug dissolution in the aqueous GI fluids, and finally what influence these variables exert on absorption once the drug is in solution.

One important property of GI fluids is pH, which varies considerably along the length of the tract. The gastric fluids are highly acidic, usually ranging from pH 1 to pH 3.5. There appears to be a diurnal cycle of gastric acidity, the fluids being more acidic at night and pH fluctuating during the day, primarily in response to food ingestion. Gastric fluid pH generally increases when food is ingested and then slowly decreases over the next several hours, fluctuating from pH 1 to about pH 5 (58). There is considerable intersubject variation, however, in GI fluid pH, depending on the general health of the subject, the presence of local disease conditions along the tract, types of food ingested, and drug therapy. Upper GI fluid pH appears to be independent of gender.

An abrupt change in pH is encountered when moving from the stomach to the small intestine. Pancreatic secretions (200-800 mL/day) have a high concentration of bicarbonate, which neutralizes gastric fluid entering the duodenum and thus helps regulate the pH of fluids in the upper intestinal region. Neutralization of acidic gastric fluids in the duodenum is important to avoid damage to the intestinal epithelium, prevent inactivation of pancreatic enzymes, and prevent precipitation of bile acids, which are poorly soluble at acid pH. The pH of intestinal fluids gradually increases when moving in the distal direction, ranging from approximately 5.7 in the pylorus to 7.7 in the proximal jejunum. The fluids in the large intestine are generally considered to have a pH of between 7 and 8.

GI fluid pH may influence drug absorption in a variety of ways. Since most drugs are weak acids or bases, and since the aqueous solubility of such compounds is influenced by pH, the rate of dissolution from a dosage form, particularly tablets and capsules, is dependent on pH. This is a result of the direct dependence of dissolution rate on solubility, as discussed in chapter 4. Acidic drugs dissolve most readily in alkaline media and, therefore, will have a greater rate of dissolution in intestinal fluids compared with gastric fluids. Basic drugs will dissolve most readily in acidic solutions and, thus, the dissolution rate will be greater in gastric fluids compared with intestinal fluids. Since dissolution is a prerequisite step to absorption and often the slowest process, especially for poorly water-soluble drugs, pH will exert a major influence on the overall absorption process. Furthermore, since the major site of drug absorption is the small intestine, it would seem that poorly soluble basic drugs (e.g., dipyridamole, ketaconazole, and diazepam) must first dissolve in the acidic gastric fluids to be well absorbed from the intestine, as the dissolution rate in intestinal fluids will be low. In addition, the disintegration of some dosage forms, depending on their formulation, will be influenced by pH if they contain certain components (e.g., binding agents or disintegrants) whose solubility is pH-sensitive. Several studies (59) have indicated that if the specific products being examined were not first exposed to an acidic solution, the dosage form would not disintegrate and thus dissolution could not proceed.

A complication here, however, is noted with those drugs that exhibit a limited chemical stability in either acidic or alkaline fluids. Since the rate and extent of degradation is directly dependent on the concentration of drug in solution, an attempt is often made to retard dissolution in the fluid where degradation is seen. There are preparations of various salts or esters of drugs (e.g., erythromycin) that do not dissolve in gastric fluid and thus are not degraded there, but they dissolve in intestinal fluid prior to absorption. A wide variety of chemical derivatives or salt forms are used for such purposes. In addition, there are numerous polymers that may be used to coat granules or tablets and that only dissolve at the desired pH, offering protection from degradation at other pHs (e.g., enteric-coated products).

As mentioned previously, pH will also influence the absorption of an ionizable drug once it is in solution, as outlined in the pH-partition hypothesis. All drugs, however, are best absorbed from the small intestine regardless of pKa and pH. In some instances, especially lower down in the GIT, there is the possibility of insoluble hydroxide formation of a drug or insoluble film formation with components of a dosage form that reduces the extent of absorption of, for example, aluminum aspirin (in chewable tablets) (60,61) and iron (62). The coadministration of acidic or alkaline fluids with certain drugs may exert an effect on the overall drug absorption process for any of the foregoing reasons.

Moreover, in addition to pH considerations, the GI fluids contain various materials which have been shown to influence absorption, particularly bile salts, enzymes, and mucin. Bile salts, which are highly surface active, may enhance the rate and/or extent of absorption of poorly water-soluble drugs by increasing the rate of dissolution in the GI fluids. This effect has been noted in in vitro experiments and has also been seen with other natural surface-active agents (e.g., lysolecithin). Increased absorption of the poorly water-soluble drug griseofulvin after a fatty meal (63,64) reflects the fact that bile is secreted into the gut in response to the presence of fats, and the bile salts that are secreted increase the dissolution rate and absorption of the drug.

Since intestinal fluids contain large concentrations of various enzymes needed for digestion of food, it is reasonable to expect certain of these enzymes to act on a number of drugs. Pancreatic enzymes hydrolyze chloramphenicol palmitate. Pancreatin and trypsin are able to deacetylate N-acetylated drugs, and mucosal esterases appear to attack various esters of penicillin. Oral cocaine ingestion is generally ineffective in producing a pharmacological response because of efficient hydrolysis by esterase enzymes in the gut. This is not true at very large doses, however, such as those resulting from the rupture of bags containing the drug, which are ingested to avoid detection at international borders (severe toxicity and death are often observed).

Mucin, a viscous mucopolysaccharide that lines and protects the intestinal epithelium, has been thought to bind certain drugs nonspecifically (e.g., quarternary ammonium compounds) and thereby prevent or reduce absorption. This behavior may partially account for the erratic and incomplete absorption of such charged compounds. Mucin may also represent a barrier to drug diffusion prior to reaching the intestinal membrane.

Gastric Emptying

Physiologists have for many years been interested in factors that influence gastric emptying and the regulatory mechanisms controlling this process. Our interest in gastric emptying is based on the fact that, since most drugs are best absorbed from the small intestine, any factor that delays movement of drug from the stomach to the small intestine will influence the rate (and possibly the extent) of absorption and therefore the time needed to achieve maximal plasma concentrations and pharmacological response. As a result, and in addition to rate of dissolution or inherent absorbability, gastric emptying may represent a limiting factor in drug absorption. Only in those rare instances where a drug is absorbed by a specialized process in the intestine will the amount of drug leaving the stomach exceed the capacity of the gut to absorb it.

Gastric emptying is determined with a variety of techniques using liquid or solid meals or other markers. Gastric emptying is quantitated by one of several measurements, including emptying time, emptying half-time (t50%), and emptying rate. Emptying time is the time needed for the stomach to empty the total initial stomach contents. Emptying half-time is the time it takes for the stomach to empty one-half of its initial contents. Emptying rate is a measure of the speed of emptying. Note that the last two measures are inversely related (i.e., the greater the rate, the smaller the value for emptying half-time).

Gastric emptying and factors that affect that process need to be understood because of the implications for drug absorption and with regard to optimal dosage form design (65). Gastric-emptying patterns are distinctly different depending upon the absence or presence of food. In the absence of food, the empty stomach and the intestinal tract undergo a sequence of repetitious events referred to as the interdigestive migrating motor (or myoelectric complex, MMC) (66). This complex results in the generation of contractions beginning with the proximal stomach and ending with the ileum. The first of four stages is one of minimal activity that lasts for about one hour. Stage 2, which lasts 30 to 45 minutes, is characterized by irregular contractions that gradually increase in strength leading to the next phase. The third phase, while only lasting 5 to 15 minutes, consists of intense peristaltic waves, which results in the emptying of all remaining gastric contents into the pylorus. The latter phase is sometimes referred to as the "housekeeper" wave. The fourth stage represents a transition of decreasing activity, leading to the beginning of the next cycle (i.e., stage 1). The entire cycle lasts for about two hours. Thus, a solid dosage form ingested on an empty stomach will remain in it for a period dependent on time of dosing relative to the occurrence of the housekeeper. The gastric residence time of a solid dosage form will vary from perhaps 5 to 15 minutes (if ingested at the beginning of the housekeeper) to about two hours or longer (if ingested at the end of the house-keeper wave). It would not be surprising, however, for gastric residence time to be substantially longer. This variability in gastric residence time may explain some of the intersubject variation in rate of absorption, and it raises some question concerning the term, "ingested on an empty stomach." While it is quite common in clinical research studies for a panel of subjects to ingest a solid test dosage form following an overnight fast and, therefore, on an "empty stomach," it is unlikely that all subjects will be in the same phase of the migrating motor complex. It is the latter point, rather than an empty stomach per se, which will determine when emptying occurs and, consequently, when drug absorption is initiated.

The above considerations will not apply to liquid dosage forms, however, which are generally able to empty during all phases of the migrating motor complex.

Various techniques have been used to visualize the gastric emptying of dosage forms. Radiopaque tablets were found to undergo relatively mild agitation in the stomach, a point that needs to be considered in the design and interpretation of disintegration and dissolution tests. While single large solid dosage forms (e.g., tablets and capsules) rely on the housekeeper wave for entry into the small intestine, some controversy remains about the influence of particle (or pellet) size (diameter and volume), shape, and density on gastric emptying. There has been a great deal of recent interest in this issue, which has been investigated primarily with use of ^-scintigraphy (a g-emitting material is ingested and externally monitored with a g-camera). These studies are generally performed with the use of nondisintegrating pellets so that movement throughout the tract may be estimated. Particles as large as 5 to 7 mm may leave the stomach. It is likely that a range of particle sizes will empty from the stomach, rather than there being an abrupt cutoff value. The range of values among individuals will be affected by the size of the pylorus diameter and the relative force of propulsive contractions generated by the stomach. The interest in this issue stems from the desire to develop sustained-release dosage forms that would have sufficient residence time in the GIT to provide constant drug release over an extended time. Experimental dosage forms that have been investigated include floating tablets, bioadhesives (that attach to the gastric mucosa), dense pellets, and large dimension forms.

Eating interrupts the interdigestive migrating motor complex. Gastric emptying in the presence of solid or liquid food is controlled by a complex variety of mechanical, hormonal, and neural mechanisms. Receptors lining the stomach, duodenum, and jejunum, which assist in controlling gastric emptying, include mechanical receptors in the stomach, which respond to distension; acid receptors in the stomach and duodenum; osmotic receptors in the duodenum, which respond to electrolytes, carbohydrates and amino acids; fat receptors in the jejunum; and L-tryptophan receptors. Neural control appears to be through the inhibitory vagal system. Hormones involved in controlling emptying include cholecystokinin and gastrin, among others.

As food enters the stomach the fundus and body regions relax to accommodate the meal. Upon reaching the stomach, food tends to form layers that are stratified in the order in which the food was swallowed, and this material is mixed with gastric secretions in the antrum. Nonviscous fluid moves into the antrum, passing around any solid mass. Gastric emptying will begin once a considerable portion of the gastric contents becomes liquid enough to pass the pylorus. Peristaltic waves begin in the fundus region, travel to the pre-pyloric area, and become more intense in the pylorus. The antrum and pyloric sphincter contract, and the proximal duodenum relaxes. A moment later the antrum relaxes and the duodenum regains its tone. The pyloric sphincter will remain contracted momentarily to prevent regurgitation, and the contents in the duodenum are then propelled forward. Emptying is accomplished by the antral and pyloric waves, and the rate of emptying is regulated by factors controlling the strength of antral contraction. Gastric emptying is influenced primarily by meal volume, the presence of acids, certain nutrients, and osmotic pressure. Distension of the stomach is the only natural stimulus known to increase the emptying rate. Fat in any form in the presence of bile and pancreatic juice produces the greatest inhibition of gastric emptying. This strong inhibitory influence of fats permits time for their digestion, as they are the slowest of all foods to be digested. Meals containing substantial amounts of fat can delay gastric emptying for three to six hours or more. These various factors appear to alter gastric emptying by interacting with the receptors noted earlier.

Other than meal volume per se, all the other factors noted earlier result in a slowing of gastric emptying (e.g., nutrients, osmotic pressure, and acidity). It is important to recognize that there are a host of other factors, which are known to influence emptying rate. Thus, a variety of drugs can alter absorption of other drugs via their effect on emptying. For example, anticholinergics and narcotic analgesics reduce gastric-emptying rate, while metoclopramide increases that rate. A reduced rate of drug absorption is expected in the former instance and an increased rate in the latter. The following factors should also be recognized: body position (reduced rate lying on left side), viscosity (rate decreases with increased viscosity), and emotional state (reduced rate during depression, increased rate during stress). As an illustration, one report indicates that absorption rate (and potentially, completeness of absorption) may be altered when comparing posture, lying on the left or right side (67). Acetaminophen and nifedipine absorption rates were faster when the subjects were lying on the right compared with the left side, suggesting more rapid gastric emptying. In the case of nifedipine, the extent of absorption was greater when the subjects were lying on the right side, which may be due to transient saturation of a presystemic metabolic process (see "Metabolism and Transporters" section). Miscellaneous factors, whose exact effect on emptying may vary, include gut disease, exercise, obesity, gastric surgery, and bulimia.

Many investigators have suggested that gastric emptying takes place by an exponential (i.e., first-order kinetic) process. As a result, plots of log volume remaining in the stomach versus time will provide a straight-line relationship. The slope of this line will represent a rate constant associated with emptying. This relationship is not strictly log linear, however, especially at early and later times, but the approximation is useful in that one can express a half-time for emptying (t50%). Hopkins (68) has suggested a linear relationship between the square root of the volume remaining in the stomach and time. There may be a physical basis for this relationship, since the radius of a cylinder varies with the square root of the volume and the circumferential tension is proportional to the radius. Methods for analyzing gastric-emptying data have been reviewed (69).

Gastric-emptying rate is influenced by a large number of factors, as noted earlier. Many of these factors account for the large variation in emptying among different individuals and variation within an individual on different occasions. Undoubtedly, much of this variation in emptying is reflected in variable drug absorption. Although gastric emptying probably has little major influence on drug absorption from solution, emptying of solid dosage forms does exert an important influence on drug dissolution and absorption. A prime example is enteric-coated tablets, which are designed to prevent drug release in the stomach. Any delay in the gastric emptying of these forms will delay dissolution, absorption, and the onset time for producing a response. Since these dosage forms must empty as discrete units, the drug is either in the stomach or the intestine. The performance of this dosage form can be seriously hampered if it is taken with or after a meal, as emptying is considerably delayed. Furthermore, if the drug is to be taken in a multiple-dosing fashion, there is a possibility that the first dose will not leave the stomach until the next dose is taken, resulting in twice the desired dose getting into the intestine at one time. Blythe et al. (70) administered several enteric-coated aspirin tablets containing BaSO4 and radiologically examined emptying of these tablets. The tablets emptied in these subjects anywhere from 0.5 to 7 hours after ingestion. Tablets will empty more rapidly when given prior to a meal compared with administration after a meal. One potential way of minimizing the impact of gastric emptying and release pattern of enteric-coated products is to use capsules containing enteric-coated microgranules. The median time for 50% and 90% emptying of such a dosage form has been shown to be 1 and 3 to 3.5 hours, respectively (71).

Several publications have reviewed the effects of food on drug absorption in humans (72-74) and have offered approaches to predicting food effects (75,76). The effect of food on the GI absorption of drugs is complex and multidimensional, and we are only now beginning to unravel the interplay of numerous variables. The physical presence of food in the GIT may play a significant role in affecting the efficient absorption of a drug from an oral dosage form. The ultimate effect of food on the rate and/or extent of GI absorption is a function of numerous interacting variables. While some general rules may be postulated, the effect of food on a given drug and its dosage form will require, in general, individual investigation. The Food and Drug Administration (FDA) has recognized this complexity and requires that all dosage forms that do not immediately release drug (e.g., controlled-release formulations) undergo a food effects study in humans, for which a "Guidance" has been written (these are available on the FDA Web page, http://www.fda.gov/). The precedence for this requirement is the observation that a sustained-release formulation may "dose dump" its entire contents of drug in the presence of food, and, since the dose is several times the usual single dose, this may lead to toxicity (77,78). The reason for this effect is related to a failure in the controlled-release mechanism (e.g., a film coating dissolves too rapidly in response to the presence of food).

The extent to which food will alter absorption depends upon factors such as physical and chemical characteristics of the drug (e.g., aqueous solubility, Ko/w, and stability in gut fluids), role of transporters and gut wall enzymes, dose of the drug, characteristics of the dosage form, time of drug administration relative to food ingestion, amount of food, and type of food. When food affects drug absorption, it most often does so by affecting the factors influencing drug dissolution or membrane transport. Other mechanisms may also apply depending on the specific drug (e.g., instability and complexation). It is useful to consider the most important rate-limiting steps in drug absorption in conjunction with what has become known as the "Biopharmaceutical Classification System" (BCS). The latter, illustrated in Figure 11, attempts to classify drugs in terms of their aqueous solubility and membrane permeability and, from that classification, predict the most likely behavior of the drug with regard to absorption following oral administration. The FDA is now using this approach in establishing regulatory standards for new drug entities and for

Figure 11 Illustration of the "Biopharmaceutical Classification System" (BCS), which classifies drug absorption potential on the basis of aqueous solubility or membrane permeability. Source: Courtesy of Saguaro Press.

generic versions of marketed drugs. The BCS can be easily understood from the simple 2 x 2 matrix illustrated in Figure 11. Drug behavior with respect to aqueous solubility and membrane permeability may be described by one of four possible conditions noted as I to IV. The effects of food on the absorption behavior of compounds classified according to the BCS has been discussed thoroughly (73,76), and they will be highlighted below.

More recently the BCS approach has been modified and expanded to include consideration of the disposition properties of drugs. This new paradigm, referred to as the "Biopharmaceutical Drug Disposition Classification System" (BDDCS), expands considerably the overall usefulness of attempts to classify drugs to better explain and predict their behavior (79,80). The BDDCS is shown in pictorial form in Figure 12. Notice that the system fits into the same basic 2 x 2 BCS matrix, which considers the primary limiting steps in drug absorption, aqueous solubility and membrane permeability. However, the BDDCS also offers information about the elimination mechanism, the presence and type of gut transporters, and the anticipated effect of food on drug absorption. This classification system will undoubtedly find many useful applications as it is further developed and fine-tuned.

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