The Proceedings of the American Thoracic Society 1:338-344 (2004)
© 2004 The American Thoracic Society
The Lungs as a Portal of Entry for Systemic Drug Delivery
John S. Patton,
C. Simone Fishburn and
Jeffry G. Weers
Research Department, Nektar Therapeutics, San Carlos, California
Correspondence and requests for reprints should be addressed to John S. Patton, Ph.D., Nektar Therapeutics, Research Department, 150 Industrial Road, San Carlos, CA 94070. E-mail: jpatton{at}ca.nektar.com
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ABSTRACT
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The lung is naturally permeable to all small-molecule drugs studied and to many therapeutic peptides and proteins. Absorption can be estimated using a simple animal test, intratracheal instillation. Inhalation offers a noninvasive route for the delivery of peptides and proteins that otherwise must be injected. Peptides that have been chemically altered to inhibit peptidase enzymes exhibit very high bioavailabilities by the pulmonary route. Natural mammalian peptides, less than about 30 amino acids, are broken down in the lung by ubiquitous peptidases and have very poor bioavailabilities. In general, proteins with molecular weights between 6,000 and 50,000 D are relatively resistant to most peptidases and have good bioavailabilities following inhalation. For larger proteins the bioavailability picture is not clear. Although the lung is rich in antiproteases, aggregation of inhaled proteins will stimulate opsonization (coating) by special proteins in the lung lining fluids, which will then mark the aggregated proteins for phagocytosis and intracellular enzymatic destruction. Small peptides and proteins are absorbed more rapidly after inhalation than after subcutaneous injection. For other small molecules, inhalation is also a fast way to get into the body because drug efflux transporters and metabolizing enzymes are present in the lung at much lower levels than the gastrointestinal tract. Lipophilic small molecules are absorbed extremely fast, t1/2 (abs) approximately 1 to 2 minutes. Water-soluble small molecules are absorbed rapidly t1/2 (abs) approximately 65 minutes. Small molecules can exhibit prolonged absorption if they are highly insoluble or highly cationic. Encapsulation in slow release particles such as liposomes can also be used to control absorption.
Key Words: bioavailability • inhalation • pulmonary
This article discusses the use of the lungs for delivery of therapeutic drugs into the systemic circulation. Although inhaled drugs have been used for over 50 years to treat airway disease and are in development or being considered for the treatment of many other lung diseases, there are currently no inhaled drugs on the market for systemic disease. This is about to change. A number of companies are in advanced clinical trials with inhaled insulin, and a variety of large and small molecules are under investigation as inhaled formulations for systemic applications. For thousands of years humans have inhaled a variety of substances for systemic effect (primarily as smoke), and now the medical establishment is starting to realize the significant potential of this route of delivery. Recent advances in the development of particle technologies and devices now make it possible to formulate, stabilize, and accurately deliver almost any drug to the lungs. The more than 25 inhalation drugs on the market for treatment of lung diseases are all absorbed to some extent into the body, most of them quickly, and with very high systemic bioavailabilities.
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ADVANTAGES OF SYSTEMIC PULMONARY DELIVERY
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No noninvasive route of drug delivery provides the bioavailability of the pulmonary epithelium. The lungs are far more permeable to macromolecules than any other portal of entry into the body (1). Some of the most promising therapeutic agents are peptides and proteins, which could be inhaled instead of injected, thereby improving compliance. The lungs are even more permeable to small molecules than the gastrointestinal (GI) tract (2).
In contrast to oral delivery, where a drug can be heavily metabolized and altered by the enzymes of the gut and liver, the lungs have only a small fraction of the drug-metabolizing and efflux transporter activity of the gut and liver (3–5). Thus, small molecules can be delivered very "cleanly" and efficiently into the body through the lungs without the production of a complex array of metabolites.
No noninvasive route of delivery provides the speed of action that an inhaled drug can provide. One of the advantages of inhaled insulin is that it is more rapidly absorbed than subcutaneously injected insulin and provides a more physiological response to a meal (6). Small molecules, particularly hydrophobic molecules, are absorbed within seconds after inhalation and can thus be used to treat a wide variety of symptoms that come on suddenly or beg for a quick response. Pain, panic, anxiety, nausea, cardiovascular crises, bronchoconstriction, sleep induction, spasms, Parkinson's lock-up, and hot flashes are some of the rapid-onset conditions that are addressable with inhaled medicines (7–9).
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PRACTICAL ISSUES WITH PULMONARY DRUG DELIVERY
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Before discussing the absorption of different drugs, it is important to mention some practical issues with inhalation delivery. To get a drug efficiently into the lungs it must be inhaled as particles with aerodynamic diameters somewhere between 1 and 3 µm. Each particle will contain billions of small molecules or hundreds of millions of macromolecules like insulin. How the patient inhales and the size of the aerosol will determine if the drug particles deposit primarily in the conducting airways (trachea, bronchi, and bronchioles) or in the alveoli. There is no evidence that large aerosol particles are absorbed intact—they must dissolve for the drug to be absorbed. In the last 20 years many advances have been made in the design of particles and devices to deliver therapeutic aerosols reliably, and with lung deposition efficiencies between 30 and 60% of what is loaded into the device (10, 11). Material that does not reach the lungs is deposited in the device or oropharynx of the patient.
The most significant barrier to absorption of inhaled drugs is the epithelium of the lung (1). It is thick (50–60 µm) in the trachea, but diminishes in thickness to an extremely thin 0.2 µm in the alveoli. The change in cell types and morphology going from trachea, bronchi, and bronchioles to alveoli is very dramatic. Though today's delivery systems have become relatively reliable and efficient at getting drugs into the lungs, no matter what the delivery system it is usually certain that some drug will always be deposited on all the different epithelial surfaces in the lung. Many small molecules, especially hydrophobic ones, are absorbed rapidly and quantitatively—probably more rapidly from the alveoli. For larger molecules such as proteins and peptides, airway epithelial junctions may be leakier than those in alveoli (1); the greater the fraction of drug deposited in the alveoli or deep lung, the higher the bioavailability for macromolecules like insulin (6). For all drugs, plasma profiles resulting from inhaled drugs are a composite of drug absorbed across markedly different epithelia, and at this time it is very difficult to know what roles the different cells play in the absorption process.
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INHALED PEPTIDES AND PROTEINS
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One of the most promising applications of inhalation technologies is the systemic delivery of therapeutic peptides and proteins that must otherwise be given by injection (12). For reasons that are not well understood, the deep lung provides higher bioavailability for macromolecules than any other noninvasive port of entry (1). Although inhaled peptides and proteins are not yet commercially available for patients to treat systemic diseases, several are in clinical trials and leuprolide, a luteinizing hormone–releasing hormone (LHRH) analog completed human clinical and safety studies for FDA approval. Inhaled insulin is in development by at least five major company groups. Insulin is absorbed from the lungs in a kinetically more advantageous manner than from the subcutaneous injection site (6). It is more rapidly absorbed and cleared from the lungs, which makes coordinating insulin dosing with meals easier for diabetics.
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ANIMAL TESTS FOR PEPTIDE AND PROTEIN ABSORPTION
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Unfortunately, unlike many other routes of delivery where the delivered dose is easy to measure, determining the mass of drug delivered to the lungs by aerosol is rather complicated. Besides having variable deposition in devices, inhaled aerosols can deposit in the nose, mouth, throat, upper and lower airways, and deep lung, and then some can escape during exhalation. In humans, the dose delivered to the lungs can be estimated by using radiolabeled aerosols. In animal absorption studies, killing immediately after aerosol exposure and lung lavage can be used to estimate the amount of drug deposited following aerosol exposure.
We and others have used the intratracheal instillation technique as a method for measuring the pulmonary absorption of molecules (1). In this technique, rats (or other animals) are lightly anesthetized and a solution of drug is injected into their lungs at the bifurcation of the trachea from a blunt hypodermic needle that has been passed through the mouth and larynx. Blood is then taken at intervals and the absorption profile is analyzed. In the intratracheal method a small fraction of the lung (< 5%) is encountered by the instilled solution. It is important, at least for molecules the size of insulin or smaller, that the instillate not be hypotonic, or else osmotic damage to the lungs may cause abnormally high absorption (13). In large animals like dogs it is also important that sufficient volumes and instillation depths are used to ensure that the majority of drug gets into alveolar spaces; otherwise, absorption may be greatly underestimated (14). In studies with 250- to 300-g rats, the bioavailability of insulin has been measured using instillation volumes of 10, 100, and 300 µl (15–17). Similar bioavailabilities (12–15%) were seen in all studies. When compared with absorption from subcutaneous injection, the bioavailability from the pulmonary route can be calculated by comparing the dose-adjusted areas under the serum concentration–time curves.
The advantages of the intratracheal method are that it is inexpensive, fast, requires smaller amounts of drug relative to aerosol studies, the dose delivered is easily measured, and it is not complicated by deposition at and absorption from other sites in the body (e.g., nose, throat, gastrointestinal system). The disadvantages of intratracheal instillation are that it often underestimates the extent of absorption that can be achieved by aerosol (18–22) and it can, with some proteins, give times to maximum blood levels (tmax) that are longer than those following aerosol delivery (19). Despite these drawbacks, the intratracheal technique is widely used, and there is a growing comparative database on which to judge some unifying principles of pulmonary absorption.
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BIOAVAILABILITY
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The bioavailability of peptides and proteins is 10 to 200 times greater by the pulmonary route as compared with other noninvasive routes. Nonetheless, when absorption is expressed per unit of absorptive surface, and relative to other absorptive epithelia in the body, the lung does not appear to be particularly permeable to macromolecules (1). However, its tremendous absorptive surface at the air interface is covered by an extremely small volume of fluid (10–20 ml) and the entire cardiac output rushes through its capillary network, which lies fractions of a micron beneath the absorptive surface (1). This means that an inhaled aerosol can be widely dispersed and deposited in quite high concentrations in close proximity to the bloodstream. Like the interior of the body, the surface fluids of the lung contain antiproteases that inhibit the enzymatic breakdown of proteins. Unlike the nasal passages and gastrointestinal tract, where rapid lateral movement of bulk fluid occurs, the alveoli of the deep lung are cul-de-sacs where residence times of molecules at the absorptive surface may be prolonged.
Table 1 lists the relative bioavailabilities determined by the intratracheal method for a series of peptides and proteins. Natural peptides less than about 30 amino acids (e.g., somatostatin, vasoactive intestinal peptide [VIP], and glucagon), and proteins (more than 30 amino acids) are susceptible to hydrolysis by different classes of enzymes. "Natural" refers to peptides and proteins that are normally found in the mammalian body. Natural peptides are readily broken down by abundant peptidases in the body. These enzymes are anchored in the plasma membranes of all cells and attack peptides at the ends of the amino acid chain, releasing one or two amino acids at a time. Proteins are usually poor substrates for peptidases, partly because the ends of their amino acid chains are often tucked into the globular structure of the protein and are not available for hydrolysis. In addition, the large size of proteins may preclude their fit into the catalytic clefts of the peptidase structures. Thus, proteins can move about the body through the circulatory system and in the interstitium of tissues and remain "resistant" to peptidases that reside on the surfaces of all vessels, cells, and epithelial surfaces.
Proteins are hydrolyzed by a different class of enzymes (i.e., proteases), which are strictly controlled in the body. In most cases the breakdown of proteins in the body occurs inside cells in specialized organelles (endosomes, lysosomes). Bodily fluids are rich in protease inhibitors (except gastrointestinal fluids), and proteases are released into nondigestive body fluids only in very specialized and localized situations such as the remodeling of damaged tissue or in the case of inflammation during infections.
Protein digestion usually occurs inside cells that engulf foreign particles (e.g., macrophages). The release of proteases into the lung fluids by immune cells usually only occurs during infection and chronic inflammation. If not controlled, protease release can cause the eventual destruction of the lung (such as with cystic fibrosis or emphysema).
There is a complex relationship between bioavailability and molecular weight of peptides and proteins (1). Natural peptides less than 3,000 D (e.g., somatostatin, VIP, and glucagon) are degraded in the lung and cannot be detected in the systemic circulation after pulmonary delivery. Table 1, however, shows the high bioavailabilities of "blocked" peptides, most of which are very successful therapeutic agents (e.g., the first six peptides in Table 1). These peptides resist peptidases either because they are linked into a ring like cyclosporin (and thus have no exposed ends) or they have chemical modifications of their C or N terminal ends which block peptidase attack. Most of these peptides were derived from natural peptides that were too peptidase-sensitive to make them useful therapeutic drugs. In the body, small peptides are used as specialized hormones, neurotransmitters, and other cell effector agents in very restricted areas, usually between adjacent cells. They are quickly broken down by the body's ubiquitous peptidases so that their activity is localized. Calcitonin is partially resistant to peptidases by virtue of a cyclic ring on one end of the molecule. Clearly, susceptibility to enzymes is one of the most powerful determinants of a peptide's bioavailability through the lungs, and the use of blocking chemistry can make an ineffective peptide into one with high bioavailability and great medical value.
As a group, the natural cytokines and growth factors including interferon-
(IFN-), human growth hornome (hGH), and granulocyte colony-stimulating factor (GCSF) (molecular weight 18,000–33,000 D), exhibit some of the highest bioavailabilities for peptides and proteins (Table 1). In the body, these molecules are designed to be able to travel long distances from their sites of synthesis. Mechanisms exist to enable them to travel across endothelia to reach cells outside the circulatory system.
The bioavailability of larger proteins via the pulmonary route is less certain. The intratracheal bioavailability of the two proteins in Table 1 with MWs > 50,000 D, appears to be low (< 5%). There is no obvious reason why inhaled large proteins should have low bioavailabilities. Transport in the opposite direction, from the blood into the airspaces, includes most proteins in plasma. Alveolar macrophages, which are technically "outside the body," produce a variety of protein cytokines and other factors that must be absorbed in order to communicate with the systemic immune system. The composition of lung epithelial lining fluids includes most of the proteins in plasma although these are present at about 1 to 10% of the concentrations found in blood (1). Very large proteins (> 300,000 D) are absent or in very low concentrations relative to plasma (23), so there is probably an upper size limit, above which proteins from the interstitium cannot easily get into the airspaces.
One possible cause of low bioavailability of larger proteins is precipitation or aggregation in the alveolar lining fluid. As an aerosol particle settles in the lung, it contacts and is enveloped by at least a monolayer of lung surfactant. Any aggregates of undissolved protein will be opsonized (coated) with various immune and nonimmune proteins that mark a particle for macrophage ingestion that, in the case of proteins, usually means enzymatic degradation (24). Because larger proteins are slowly absorbed by the lungs, they have a long time to clump and aggregate and be cleared by the alveolar macrophages.
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PEPTIDE AND PROTEIN ABSORPTION
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The time it takes natural peptides and proteins to peak in the blood after pulmonary delivery is molecular weight–dependent; the larger the size, the slower the absorption. Small soluble blocked peptides peak in the blood in 10 to 30 minutes. Large proteins peak in hours to days (Table 1). However, with blocked peptides, some of which are also lipophilic or poorly water soluble (e.g., cyclosporine, detirelix), dissolution may be the rate-limiting step in absorption. An important comparative result with blocked peptides is the difference in tmax between leuprolide (0.37 hours) and the more lipophilic, detirelex (7.6 hours) (12, 25). Both molecules have the same therapeutic effect yet different absorption profiles. This shows that peptide absorption rates through the lung can be manipulated by chemistry. As with small molecules, small peptides and proteins (> 6,000 D) are usually absorbed faster after inhalation than after subcutaneous injection. For example, regular insulin has been shown to peak in the blood in humans after aerosol delivery at 5 to 60 minutes as compared with 60 to 180 minutes after subcutaneous injection (6). The situation with larger macromolecules is not clear, and in the case of heparin (mean molecular weight 15,000 D), the absorption after aerosol delivery to humans is more sustained and prolonged than by subcutaneous injection (26). Animal experiments have suggested that heparin is stored in pulmonary epithelial cells and macrophages (26).
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RELEVANCE OF INTRATRACHEAL RESULTS TO AEROSOLS IN ANIMALS AND HUMANS
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Bioavailabilities determined by the intratracheal method underestimate pulmonary bioavailabilities that can be achieved by aerosol administration. Presumably this is partly because intratracheal instillation provides access to a very small fraction of the lung's absorptive surface (< 5%). Table 2 shows a comparison of the relative bioavailabilities of four proteins measured by the two techniques. It is important to note that these bioavailabilities are based on the absorption of the drug amount that was deposited in the lungs. Traditional aerosol devices can only deliver about 10 to 20% of their loaded doses into the lungs. Thus, if a protein has an in-lung aerosol bioavailability of 50%, but the device that is used to deliver the protein has a delivery efficiency of only 10%, then the overall delivery efficiency (bioavailability from the device) will be 5%. Analyses of numerous studies of aerosol insulin delivery to normal humans suggests that the mouth-to-blood bioavailability of regular insulin is about 20 to 40% (6).
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MECHANISMS OF ABSORPTION
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The precise mechanisms of macromolecule absorption in the lungs are not well known. Most exogenous macromolecules are thought to be absorbed from the airspaces nonspecifically through a combination of tight junctions and endocytic vesicles by processes that are diffusion-limited (1). Thus a large molecule takes longer to find its "opening" than a small molecule simply because the large molecule's random walk is at a slower pace than the small molecule. But the picture may be more complex. There is evidence that for certain endogenous molecules that normally occur in lung lining fluids, e.g. albumin (27), immunoglobulins (28) and transferrin (29), there are specific receptor-mediated transport mechanisms on the alveolar epithelial cell that enable these proteins to be absorbed at higher rates than expected.
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SMALL MOLECULE DRUG ABSORPTION
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Most small molecules that have some water solubility are rapidly and efficiently absorbed from the lungs. Those that are more hydrophobic are absorbed even more rapidly—within seconds to a few minutes. Those that are more hydrophilic are absorbed within minutes to tens of minutes. Lewis Schanker and colleagues, in a series of papers between 1973 and 1986 (30–45), explored many facets of pulmonary drug absorption in a variety of different animals. They quantitatively analyzed the amount of radiolabeled drug absorbed across the pulmonary epithelium following intratracheal and aerosol delivery and determined the comparative rates of absorption for different classes of compounds. They compared the characteristics between different species, sexes, and ages of animals and determined the effect of various noxious agents that damage epithelia on pulmonary absorption.
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HYDROPHOBIC VERSUS HYDROPHILIC SMALL MOLECULES
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Table 3 provides a summary of a subset of the different molecules studied by Schanker and colleagues (30–45). The observed trend in half-life with lipophilicity (as estimated from the octanol-water partition coefficient, log P) is captured in Figure 1. A natural break seems to occur for compounds that are hydrophilic (lipid insoluble, log P < 0), and lipophilic (lipid soluble, log P > 0). Hydrophilic materials cluster around a mean half-life of about 1 hour, whereas lipophilic drugs cluster around a half-life of about 1 min. Interestingly, there does not seem to be a strong dependence of the half-life with log P, other than the clustering which occurs for the two classes of molecules. That is, decreasing log P from 0 to –5.0 results in little deviation in the measured half-life. Similarly, increasing log P from 0.0 to 4.0 results in no discernable difference. Absorption of lipophilic molecules appears to be nonsaturable over a wide concentration range. Certain molecules classified as lipid-soluble by Schanker and coworkers are absorbed more slowly than might be expected, based on their classification. These include tetracycline and sulphaguanidine, and ethambutol. Each of these molecules had a log P < 0 indicating that they possessed significant hydrophilic character. Erythromycin was also absorbed more slowly than one might expect despite its log P value of 3.06. Erythromycin and other macrolides have been shown to interact with phospholipids (50), and such an interaction with lung lipids may slow absorption of this class of antibiotics through the lung.
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TABLE 3. The effect of molecular weight and lipophilicity on the rate of absorption of small molecules following intratracheal instillation in rats (30–45)
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Figure 1. Pulmonary absorption data from Schanker and colleagues (30–45), demonstrating that the rate of drug absorption from the lungs is dependent on drug lipophilicity. Here, t1/2 represents the time taken for absorption of 50% of the initial dose through the lung following intratracheal administration in rats, and log P represents the octanol-water partition coefficient. Molecules characterized by Schanker and coworkers as lipid-insoluble or as lipid-soluble are shown as squares and triangles, respectively. Molecules with active uptake are denoted by inverted triangles.
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It is interesting that within the molecular weight range from about 100 to 1,000 g/mol, there appears to be no dependence of half-life on molecular weight (Figure 2) (30–34). Again, the data seem to be classified simply on the basis of lipophilicity. More lipophilic drugs in this range pass through the lung rapidly, whereas more hydrophilic compounds pass much slower, but still fast compared with higher molecular weight compounds. Only when the molecular weight exceeds 1,000 D does the half-life increase significantly. Schanker and colleagues (30–34) examined a series of high molecular weight carbohydrates which showed, like with peptides and proteins, much slower absorption at molecular weights in the tens of thousands.
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Figure 2. Relationship between molecular weight and rate of absorption through the lung (data from Schanker and coworkers [30–45]). Molecules characterized by Schanker and colleagues as lipid-insoluble or as lipid-soluble are shown as squares and triangles, respectively. Molecules with active uptake are denoted by inverted triangles.
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MECHANISMS OF SMALL MOLECULE ABSORPTION
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Putting that data of Schanker and coworkers in the context of our current understanding of the molecular basis of transepithelial transport allows one to draw certain inferences about the potential mechanisms of absorption of the different classes of molecules. Lipid-soluble compounds are rapidly absorbed presumably because they can integrate into the lipid bilayer surrounding the cells. This constitutes the "transcellular pathway" in which compounds pass from the apical to basolateral side by traveling through the cellular membrane. Lipid-insoluble compounds, by contrast, most likely traverse the epithelium via a paracellular route, in which they pass through aqueous pores in the intercellular tight junctions. Although the nature of these junctions is not fully understood, it appears that a combination of molecular weight and degree of ionization determine the rate at which molecules can pass through. The less ionized a molecule, the faster its absorption rate, because it forms fewer interactions with the proteins and lipids that line the pore. The work of Schanker and associates (30–34) suggests that for small hydrophilic compounds in the range of 100 to 1,000 D, the degree of ionization is likely to dominate, whereas for larger ones the molecular weight becomes an influential factor, too.
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ACTIVE TRANSPORT
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A number of compounds (e.g., disodium cromoglycate and cycloleucine) undergo active or "carrier-mediated" transport (Table 4) (45). Their absorption rates are saturable, such that the percent dose absorbed decreases with increasing concentration. In addition, their absorption is energy-dependent and can be inhibited by other compounds that share common structural features. These molecules enter cells by binding to specific carrier proteins on the cell surface, and use an energy-driven exchange to drive uptake against a concentration gradient. Nonetheless, these molecules do not deviate significantly from other molecules of similar lipophilicity or molecular weight in terms of their absorption characteristics (Figures 1 and 2).
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SPECIES DIFFERENCES
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Although there appears to be no species differences in the rates of absorption of lipophilic drugs, some interspecies differences are noted with water-soluble drugs (31). Measured rates were highest in the mouse and guinea pig, slightly slower in the dog and rat, and slower yet in the rabbit (Table 5). Species comparisons demonstrated similar ranked orders of absorption rates for different compounds. There were no sex differences seen. Comparisons of rates following intratracheal instillation or by aerosol administration showed that absorption following inhalation was approximately twofold faster than by instillation, which reflects the much greater absorptive surface exposure that occurs after aerosol administration.
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TABLE 5. Species comparison of relative absorption rates of drugs from lungs following intratracheal instillation (31)
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SLOW ABSORPTION OF INHALED SMALL MOLECULES
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Although the rapid absorption of small molecules has many conceivable medical uses, there are situations when one might want to slow the absorption of an inhaled small molecule, either to keep it acting longer locally in the lung, or to regulate its absorption into the body. There appear to be at least two instances in which small molecules are much more slowly absorbed than the data of Schanker and coworkers might suggest. Very insoluble small molecules that slowly dissolve from the inhaled particle may stick in the lung for many hours or even days. Fluticasone propionate, amphotericin B, and all-trans retinoic acid are absorbed from the lungs over a period of hours (46, 47), due in part to their slow dissolution rate from relatively insoluble lipophilic particles. There may also be specific interactions (e.g., amphotericin B with endogenous sterols) that help to slow absorption.
Another instance in which soluble small molecules stay in the lungs longer than expected is the case with tobramycin and pentamidine, which are absorbed over a period of several hours following inhalation in humans (48, 49). Here the mechanism of retention may be related to the multiple positive charges on the molecules that bind to the ubiquitous negative charges on the surface of cell membranes.
The absorption of small molecules can also be slowed via encapsulation in slow release particles such as liposomes (7, 8).
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CONCLUSIONS
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Aerosol administration of therapeutics to the pulmonary epithelium for systemic delivery represents a significant opportunity for many classes of drugs, and both small molecules and macromolecules. Advantages of aerosol administration include: (1) more rapid absorption into the systemic circulation (this may be especially important for drugs where fast onset of action is critical), and (2) higher bioavailability than with other noninvasive modes of administration. This is certainly true for the delivery of peptides and proteins relative to oral administration, and is also true for many small molecules where first-pass metabolism or efflux transporters limit oral bioavailability.
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FOOTNOTES
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Nektar Therapeutics supported this work in its entirety.
Conflict of Interest Statement: J.S.P. is founder and Chief Scientific Officer for Nektar Therapeutics, has stock in the company, and received lecture fees from Boehringer Ingelheim; C.S.F. has been employed by Nektar Therapeutics since 2002 and has received compensation in the form of salary and stock options, and she and her spouse have shares in Nektar Therapeutics and Pfizer Inc.; J.G.W. was employed by Nektar Therapeutics from October 1999 to June 2004 and was compensated with salary, bonuses, benefits, and stock options during his employment.
(Received in original form September 30, 2004; )
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ABSTRACT
ADVANTAGES OF SYSTEMIC PULMONARY...
