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The Proceedings of the American Thoracic Society 1:356-363 (2004)
© 2004 The American Thoracic Society

How the Lung Handles Drugs

Pharmacokinetics and Pharmacodynamics of Inhaled Corticosteroids

Julia Winkler, Guenther Hochhaus and Hartmut Derendorf

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida

Correspondence and requests for reprints should be addressed to Hartmut Derendorf, Ph.D., P.O. Box 100494, Department of Pharmaceutics, College of Pharmacy, University of Florida, 1600 SW Archer Rd., Gainesville, FL 32610-0494. E-mail: hartmut{at}cop.ufl.edu


   ABSTRACT
TOP
 ABSTRACT
PHARMACODYNAMIC PROPERTIES
 PHARMACOKINETIC PROPERTIES
 DISCUSSION
 REFERENCES
 
Bronchial asthma and allergic rhinitis are among the most common diseases of modern society and to an increasing degree a major cause of illness, hospitalization, loss of productivity, and death. Despite improvements in drug therapy over the years, the incidence is still increasing. Inhaled and intranasal corticosteroids are the drugs of choice in the therapy of asthma and allergic rhinitis. Inhalation and intranasal use result in better, target-specific delivery of corticosteroids. Higher concentrations at the site of action and minimized systemic exposure provide improved therapeutic ratios. However, there is still considerable concern over the risk of systemic side effects. It is the goal of inhaled and intranasal corticosteroid therapy to produce long-lasting therapeutic effects at the site of action and minimize systemic side effects with high clearance, low oral bioavailability and high plasma protein binding. This article reviews the pharmacokinetic and pharmacodynamic properties of corticosteroids used in asthma and allergic rhinitis.

Key Words: allergic rhinitis • asthma • corticosteroids • pharmacodynamics • pharmacokinetics

Bronchial asthma and allergic rhinitis are among the most common chronic diseases of modern society, and despite recent advances in drug therapy the incidence is still increasing. Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements are involved. The chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment (1).

To an increasing degree, asthma is a major cause of illness, hospitalization, loss of productivity, and death. The main goals of asthma therapy are to prevent chronic symptoms, to maintain nearly normal pulmonary function, to maintain normal activity levels, and to prevent recurrent asthma exacerbations and minimize the need for hospitalizations (2).

Allergic rhinitis is caused by an inflammation within the nose in response to allergy triggers, such as pets and pollens. It leads to the typical symptoms of nasal congestion, sneezing, runny and itchy nose, and itchy, watery eyes (3). There are two different forms of allergic rhinitis: seasonal and perennial allergic rhinitis. Seasonal allergic rhinitis is triggered mainly by natural pollen exposure, whereas perennial allergic rhinitis may be caused by various environmental allergens (4). Suffering from allergic rhinitis results not only in a loss of productivity but also in a general impaired health-related quality of life.

Over the years, drug therapy of asthma and allergic rhinitis has been significantly improved, mainly due to the introduction of new corticosteroids with better pharmacokinetic properties (and therefore improved therapeutic ratios).

Inhaled and intranasal corticosteroids are the drugs of choice in the therapy of asthma and allergic rhinitis. However, there has recently been an increased awareness of their ability to produce systemic adverse effects. The availability of more potent corticosteroids and new delivery systems has focused attention on these safety issues (5). It is the goal of all inhaled and intranasal corticosteroids to (1) produce long-lasting therapeutic effects at the site of action, (2) minimize oral availability, and (3) minimize systemic side effects by rapid clearance of absorbed drug. At present there are six inhaled corticosteroids available for the treatment of asthma and/or allergic rhinitis, and others are in development. These are triamcinolone acetonide, flunisolide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone fuorate. Ciclesonide and loteprednol etabonate are still in development for inhaled and intranasal use, respectively. This article reviews their pharmacokinetic and pharmacodynamic properties, and will consider the necessary properties of an ideal topical corticosteroid for use in the treatment of asthma and allergic rhinitis.


   PHARMACODYNAMIC PROPERTIES
TOP
 ABSTRACT
 PHARMACODYNAMIC PROPERTIES
PHARMACOKINETIC PROPERTIES
 DISCUSSION
 REFERENCES
 
Receptor Binding
The pharmacodynamic properties of corticosteroids can be described by the binding of the drug to its receptor because the pharmacologic effect of corticosteroids is mediated through the glucocorticoid receptor. Due to the ubiquitous nature of the glucocorticoid receptor, corticosteroids act on a wide variety of cell types. This accounts for their systemic effects, in addition to their local therapeutic effects. The glucocorticoid receptor is located in the cytoplasm. Although there are two different types of glucocorticoid receptors, currently available glucocorticoids only bind to the type II receptor (the type I is also known as the mineralocorticoid receptor). The type II receptor is expressed in almost all tissues and cells, and the pharmacologic effects, both beneficial and unwanted, of inhaled and intranasal corticosteroids are mediated through reversible binding to this receptor. After binding to the receptor, the drug–receptor complex translocates into the nucleus, binds to DNA, and hence activates or represses gene transcription through different mechanisms. Recent research focuses on finding new glucocorticoids that will separate these transactivation and transrepression processes (6, 7).

Transactivation, the stimulation of gene transcription, was found to be correlated with several negative side effects of corticosteroids, whereas the transrepression, repression of transcription factors such as nuclear factor-{kappa}B and activator protein-1, seems to be responsible for the antiinflammatory effect (8). Important for the stimulation of transcription is the dimerization of the ligand-bound receptor. This dimerization is both necessary for high-affinity binding of the receptor to the glucocorticoid response element (GRE) and for glucocorticoid-dependent induction of gene transcription (6, 8, 9). Negative regulation by glucocorticoids can be achieved by either a direct interaction of the glucocorticoid receptor with a site on the DNA called negative GRE (nGRE) or via protein–protein interactions such as activator protein-1 and nuclear factor-{kappa}B (6, 8, 9). This new approach could be very promising in increasing the therapeutic index, but further research needs to be done to prove this concept.

Depending on their receptor-binding affinity, different drugs have different potencies. Potency is an important measure of pharmacologic action, as higher receptor affinity is associated with an increased pharmacologic response (10). However, increasing the potency of a glucocorticoid will not necessarily increase the therapeutic ratio (topical:systemic activity), as increasing the potency will lead to higher topical efficacy but at the same time also more systemic activity and a higher incidence of systemic side effects.

Table 1 and Figure 1 show relative receptor binding affinities (RRAs) for different corticosteroids used for inhalation and intranasal use (11, 12). The receptor binding affinities are usually given in comparison with an affinity of 100 for the standard dexamethasone. Mometasone fuorate (MF) is reported to have the highest receptor binding affinity (2,300), followed by fluticasone propionate (FP) (1,800) and beclomethasone monopropionate (17-BMP) (1,345) (12, 13). The active metabolite of the new corticosteroid ciclesonide, des-ciclesonide, shows also a high receptor binding affinity (1,200), while LE is reported to have a receptor binding affinity of 430 (14, 15). As receptor binding affinity can be compensated by administering dose equivalents, the pharmacokinetic properties of the corticosteroids are the more important factors to evaluate their safety and efficacy (16).


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  		TABLE 1. Pharmacokinetic and pharmacodynamic parameters of inhaled and intranasal corticosteroids

 


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  		Figure 1. Relative receptor binding affinities (RRAs) of inhaled and intranasal corticosteroids. 17-BMP = beclomethasone monopropionate; B = beclamethasone; BDP = beclamethasone dipropionate; BUD = budesonide; CIC = ciclesonide; Des-CIC = des-ciclesonide; FLU = flunisolide; FP = fluticasone propionate; LE = loteprednol etabonate; MF = mometasone fuorate; TA = triamcinolone acetonide.

 

   PHARMACOKINETIC PROPERTIES
TOP
 ABSTRACT
 PHARMACODYNAMIC PROPERTIES
 PHARMACOKINETIC PROPERTIES
DISCUSSION
 REFERENCES
 
Prodrug
A prodrug is a pharmacologically inactive compound that is activated in the body after its administration. To exert a local effect, a prodrug needs to be activated in the target tissue, e.g., lung or nose. For corticosteroids used in inhalation and intranasal therapy, activation is usually initiated by esterases in the lung/nose. This tissue selectivity also reduces the risk of local as well as systemic side effects if the esterases necessary for the activation are mainly found in the lung tissue. After inhalation of an active corticosteroid, a part of the drug is deposited in the mouth and oropharynx, leading to side effects such as oral candidiasis. Administration of an inactive prodrug may reduce the incidence of local side effects in the mouth and oropharynx region, because the inactive drug deposited in that region will be swallowed before activation can occur. This concept has been proven in studies on ciclesonide. Administration of the prodrug ciclesonide resulted in significantly less oral deposition of ciclesonide as well as its active metabolite des-ciclesonide than fluticasone propionate (17).

Desired characteristics of a prodrug are essentially no receptor binding, rapid hydrolysis to the active compound in the lung or nose, high receptor binding affinity of the active compound, and no pharmacologic effect of its secondary metabolites (16). Besides all the advantages of using inactive prodrugs, it has to be ensured that the prodrug actually is converted to the active drug after administration to avoid failure of therapy. Beclomethasone dipropionate is, so far, the only corticosteroid on the market used in the treatment of asthma and allergic rhinitis that has a prodrug structure. Beclomethasone dipropionate (BDP) has a low receptor binding affinity (RRA = 53), whereas its active form, 17-beclomethasone monopropionate, binds to the glucocorticoid receptor with a high affinity (RRA = 1,345). 17-BMP is further metabolized to beclomethasone, which has a receptor binding affinity lower than dexamethasone (RRA = 76) (see Table 1). A second drug with a prodrug structure, which is still in development for the treatment of asthma, is ciclesonide. It is administered as the prodrug and activated by esterases in the airways (18). The parent compound is 100-fold less potent in binding to the glucocorticoid receptor than the active principle des-ciclesonide.

Softdrug
Another way to target a drug is the softdrug concept. A softdrug is essentially the opposite of a prodrug. It is defined as a biologically active chemical compound characterized by a predictable and controllable in vivo metabolism to nontoxic moieties, after they achieve their therapeutic role (19). In short, the softdrug is active per se while the prodrug is inactive per se. The inactivation occurs ideally in a single step, although further metabolism of the inactive metabolite is possible (20). The metabolic inactivation occurs preferably through simple steps, e.g. hydrolysis, without the use of enzymes that could be saturated. There are several approaches to design soft drugs. One example of the inactive metabolite approach is loteprednol etabonate. It was designed by using the known inactive metabolite cortienic acid of hydrocortisone as a lead compound. Appropriate structural changes led to the active compound loteprednol etabonate that is again inactivated in a single metabolic step.

Bioavailability
The pharmacokinetic properties of the corticosteroid as well as the application device and technique determine how much steroid will reach the sites of desired and undesired activity and how long it will stay there. Important aspects are bioavailability and drug formulation.

The bioavailability of an inhaled/intranasal corticosteroid is the rate and extent at which the drug reaches its site of action (pulmonary/nasal bioavailability) as well as the blood (systemic bioavailability).

After inhalation, a large part (approximately 40–90%) of the dose is swallowed and subsequently available for systemic absorption. This bioavailability of the orally delivered part is dependent on absorption characteristics of the drug from the gastro-intestinal tract and the extent of intestinal and hepatic first-pass metabolism. Because the orally absorbed fraction of the drug does not contribute to the beneficial effects but can induce systemic side effects, it is desirable for the oral bioavailability of inhaled corticosteroids to be very low.

The oral bioavailabilities of currently used corticosteroids range from less than 1% for fluticasone propionate to 26% for 17-beclomethasone monopropionate (21–28). However, the main determinant of systemic bioavailability after inhalation is direct absorption from the lung, where for the currently available inhaled corticosteroids there is no first-pass effect. All of the drug that is deposited in the lung will be absorbed systemically (5). The percentage of the dose that is deposited in the lung is greatly influenced by the efficiency of the delivering device. The pulmonary bioavailability is rather a function of the delivery device used for inhalation than a property of the drug itself. The pulmonary bioavailability will depend on the amount deposited in the lungs and will differ with the delivery device used (5, 29). Fluticasone propionate, for example, has an oral bioavailability of less than 1% due to a high first-pass metabolism. When administered to the lungs using a dry powder inhaler (DPI), the absolute bioavailability (systemic + pulmonary) is reported to be approximately 17%, compared with 26 to 29% when using a metered dose inhaler (MDI) (30–32). After mometasone fuorate administration via a dry powder inhaler the absolute bioavailability was reported to be 11% (30). Table 2 summarizes the device-dependent parameters of corticosteroids such as the pulmonary and nasal bioavailabilities after inhalation and intranasal administration, respectively. Table 1 shows the systemic bioavailability after oral administration (33).


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  		TABLE 2. Device-dependent bioavailabilities after inhaled and intranasal administration of corticosteroids

 
Most of what was said for inhaled administration is also true for intranasal use. A major advantage of intranasal delivery is that the efficiency of deposition is usually high (about 80%) (11). However, following intranasal delivery there is a rapid mucociliary clearance from the nose into the throat and consequently a large proportion of the dose (~ 70%) is swallowed, which in turn can be responsible for systemic side effects after absorption from the gastrointestinal tract (5).

There are several factors influencing the degree of systemic bioavailability such as droplet size of a liquid formulation, the particle size of a suspension, the type of formulation (solution/suspension), the delivery device, and the physicochemical properties of the drug itself (11). For example, it could be shown that the bioavailability of fluticasone propionate is increased eightfold if an aqueous nasal spray is used compared to nasal drops. However, the bioavailabilities for both formulations were low, with 0.51% for the spray and 0.06% for the drops (34). The percentage of the dose that is swallowed is dependent on the lipophilicity of the drug. A high degree of lipophilicity diminishes water solubility and therefore increases the amount of drug swept away by nasociliary clearance before it can get access to the receptor sites (5). Therefore, a high degree of lipophilicity might not be favorable for a drug used for intranasal application because sufficient drug needs to be dissolved and absorbed into the target cells in the nasal mucosa in order to be effective. Estimated absolute bioavailabilities for corticosteroids after intranasal administration varies from 49% for flunisolide to 44% for beclomethasone dipropionate to 34% for budesonide to less than 1% for fluticasone propionate and mometasone fuorate (34–37). However, differences in systemic bioavailability may also arise from different delivery devices. In general, aqueous solutions seem to have higher intranasal bioavailabilities than dry powders or pressurized aerosols (38).

Drug Formulation
Another important factor in assessing the efficacy and safety of an inhaled/intranasal corticosteroid is the delivery device. Inhaled corticosteroids are administered either via a metered-dose inhaler (MDI) or via a breath-activated dry powder inhaler (DPI). The MDI contains the drug either as a suspension in a carrier liquid or a solution delivered through a chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) propellant, respectively, although CFC-MDIs are gradually being phased out because of their ozone-depleting potential (31). Additional to their environmentally friendly property, HFA solutions also seem to have the advantage of delivering a much greater mass of fine particles. Fine particles, with a diameter of less than 5 µm, are more likely to be deposited in the tracheobronchial and pulmonary regions in the lung. Larger particles on the other side are deposited mostly in the oropharynx, where they are swallowed and increase the risk of systemic absorption (39). The average particle diameter delivered by a CFC-MDI is 3.5 to 4.0 µm, whereas the average particle diameter delivered by a HFA propellant is around 1.1 µm. This difference in particle diameter might have a clinical significance, as the average diameter of small airways is around 2 µm, resulting in a greater lung deposition (40). This increased proportion of fine particles with the HFA-MDI results in an improved lung deposition. In a study using inhaled beclomethasone dipropionate, the lung deposition increased from 4 to 7% with CFC-BDP to 55 to 60% for a newly developed HFA-MDI formulation (41). A high lung deposition was also found for ciclesonide. With the CFC-free solution MDI, a mean lung deposition of 52% could be obtained (42). In a single-dose study comparing HFA flunisolide and CFC flunisolide, the drug deposition in the lung could even be increased to 68% (HFA) compared with 19.7% (CFC) (43).

Lung deposition can also be increased by use of spacer devices, which can alter the amount of fine particles and therefore increase the respirable fraction and decrease the amount of drug deposited in the oropharynx (44). However, it also needs to be kept in mind that a greater lung deposition might result in a greater possibility of systemic adverse effects because of the lack of first-pass metabolism after direct absorption from the lung. The other inhaler type used for inhalation of corticosteroids is the DPI. The DPI offers an easier delivering technique that requires less coordination than the MDI. However, it requires a forceful deep inhalation to trigger the inhalation device to help break up the aggregates of the micronized powders into respirable particles in the oropharynx and larger airways. Thus, lung deposition is flow-dependent and the higher the inhalation flow, the smaller the particles will be (45). An inspiratory flow of 60 L/minute is considered to be optimal (44). Therefore, the flow characteristic should be determined and it should be ensured that patients with asthma in all asthma stages are able to achieve an inhalation flow that is enough to achieve the required effect (45). In a lung deposition study with budesonide, it could be shown that reducing the inhalation flow from 58 L/minute to 36 L/minute reduces the lung deposition from around 28% to around 15% (46).

There have been also new developments in the field of nebulizers and liquid formulations. Among those are the inhalation device Mystic from Batelle, which is based on electro-hydrodynamic principles, employing electrostatic energy to create fine aerosols from formulated drug solutions or suspensions, thereby increasing the pulmonary tract deposition to about 80% (47); and the RESPIMAT device from Boehringer Ingelheim, which uses a high-pressure microspray system of nozzles to release a metered dose to the patient. This system generates a slow release of the drug with a high concentration of respirable particles (48).

There are also differences between the delivery devices for nasal administration. Currently there are three different devices on the market, pressurized metered dose inhaler (pMDI), aqueous pump spray, and powder. The aqueous pump spray and the powder formulations are preferred because they offer a better intranasal distribution than the pressurized aerosols (49). Compared with inhaled corticosteroids, the efficiency of intranasal drug deposition is not one of the main concerns with the devices currently in use because it is in general very high (around 80%) (11). For budesonide, for example, the intranasal bioavailability is reported to be around 66% using a dry powder inhaler (50). However, after administration a large portion of the dose is transported into the gastrointestinal tract by nasal mucociliary clearance (51). To avoid systemic side effects from the swallowed part, a low oral bioavailability and a high clearance are desirable characteristics of the drug (see BIOAVAILABILITY). As with inhaled corticosteroids, the absolute bioavailability of an intranasally administered drug is the sum of the orally absorbed portion and the portion that is absorbed directly from the nose into the systemic circulation. Absorption across the nasal mucosa varies significantly and increases with increasing water solubility of the drug (51). Therefore, highly lipophilic drugs, such as fluticasone propionate, have diminished water solubility in the nasal mucosa and increase the amount of drug swept away by mucociliary clearance before it can reach the receptor sites (5). The physicochemical state of the formulation is another important factor influencing the local and systemic concentration after nasal application (11). It could be shown that after administration of a solution-based triamcinolone acetonide product absorption is faster than after an aqueous suspension of the same drug. This might increase the local as well as the systemic concentrations after intranasal application (52).

Finally, delivery of the drug to the lung or nose does not only depend on the device itself but also on the patient, because every inhaler or nasal spray requires a certain technique for optimal drug delivery (44).

Protein Binding
Many drugs are bound to plasma proteins once they reach the systemic circulation. Binding to plasma proteins, such as albumin and transcortin, keeps the drug in the blood stream and prevents its diffusion into the tissue. Most of the synthetic corticosteroids are moderately to highly protein bound (>= 70%). Because it is understood that only the free, unbound drug is pharmacologically active, knowledge about the protein binding might be important in assessing the pharmacokinetics and pharmacodynamics of a drug. A high plasma protein binding will consequently lead to a low fraction unbound and suppression of endogenous cortisol, an important measure of systemic side effects, might become insignificant. In case of linear protein binding the plasma concentration of the free drug is a constant fraction of the total drug. However, if nonlinear protein binding occurs this issue becomes more difficult because the fraction of the unbound drug is not constant (53). Corticosteroids used for inhalation or intranasal use show linear protein binding to albumin. However, the extent of binding differs, with ciclesonide showing the highest degree of binding (99%) (54), followed by mometasone fuorate (98–99%) (55), 17-beclomethasone monopropionate (98.4% in rat plasma) (56) and fluticasone propionate (90%) (57), budesonide (88%) (26), and beclomethasone dipropionate (87%) (58). Flunisolide and triamcinolone acetonide show a lower protein binding with fractions bound of 80% (59) and 71% (60), respectively (Figure 2, Table 1). For the new corticosteroid loteprednol etabonate only data in dog plasma are available. The plasma protein binding was reported to be greater than 90% (61).



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  		Figure 2. Protein binding of inhaled and intranasal corticosteroids. BDP = beclamethasone dipropionate; BUD = budesonide; CIC = ciclesonide; Des-CIC = des-ciclesonide; FLU = flunisolide; FP = fluticasone propionate; LE = loteprednol etabonate; MF = mometasone fuorate; TA = triamcinolone acetonide.

 
Clearance
Clearance is a measure of drug elimination from the body. It is expressed as the volume of plasma or any other fluid that is completely cleared from the drug per time unit (usually L/hour). For most drugs showing linear protein binding and nonsaturated elimination, this value is a constant. If the drug is mainly metabolized and cleared by the liver, the maximal clearance a drug can reach is the rate of the liver blood flow (~ 90 L/hour). A rapid clearance after the drug enters the systemic circulation results in low systemic concentrations, minimizing the potential for systemic side effects and improving its therapeutic index.

All currently available corticosteroids for inhalation and intranasal use are cleared in the liver with values close to the liver blood flow. The clearance of such high extraction drugs is independent of protein binding. Therefore, further efforts to develop new steroids with increased intrinsic hepatic clearance is unnecessary, as such steroids will not be cleared more efficiently.

Research should rather focus on new drugs with extrahepatic elimination, as this will be the only way to further increase the clearance over the liver blood flow. Budesonide has the highest clearance rate with 84 L/hour (26), followed by fluticasone propionate (66–90 L/hour) (62, 63), flunisolide (57 L/hour) (27), mometasone fuorate (54 L/hour) (11), and triamcinolone acetonide (37 L/hour) (28). For the active metabolite 17-BMP and Des-CIC somewhat higher clearance rates (120 L/hour and 228 L/hour, respectively) have been reported (28). However, these values are calculated based on the assumption of complete conversion of the prodrug. The precise determination of their clearance values is only possible after intravenous administration of these metabolites. The clearance of loteprednol etabonate was studied in dogs and found to be 0.9 L/hour/kg, which is within the range of the other steroids (61). Currently, no human data is available. Table 1 shows the clearance values for the different corticosteroids.

Volume of Distribution
The volume of distribution is a measure of the distribution of the drug in the body. It relates the plasma concentration to the amount of the drug in the body. The lower the concentration in the plasma, the more of the drug is distributed into the tissue, resulting in a larger volume of distribution. Thus, corticosteroids with a very large volume of distribution (300–900 L) are extensively distributed and bound to the tissues. However, there is not necessarily a direct correlation between the volume of distribution of a corticosteroid and its pharmacologic activity. The pharmacologic activity depends also on the concentration of unbound drug at the site of action and its receptor binding affinity. At steady state, the unbound, free drug depends only on the clearance and the degree of protein binding, but not on the volume of distribution (10, 64). Furthermore, when comparing volume of distributions, it has to be kept in mind that the values can differ depending on the way of calculation.

The volume of distribution at steady state for the currently used corticosteroids is highest for FP (318–859 L) (10, 62, 65, 66) as well as for the active metabolites des ciclesonide (Des-CIC) (897 L) and BMP (424 L) (22). Similar to the clearance, the values of the volumes of distribution of des-CIC and BMP are based on the assumption of complete conversion from the prodrug to the active metabolite. Other volumes of distribution are 183–301 L for BUD (10, 26, 65, 67), 103 L for triamcinolone (10, 28, 65) and 96 L for flunisolide (10, 59). Reported values for the different corticosteroids are also listed in Table 1. The volumes of distribution of the inhaled corticosteroids are in accordance with the lipophilicity of those drugs. The more lipophilic the drug is, the more is distributed and bound to the tissues.

Half-Life
The half-life is the time needed for the total amount of drug in the body or the concentration of the drug in plasma to decrease by one half its value. In inhalation therapy two different half-lives can be distinguished: the elimination half-life and the terminal half-life after inhalation.

Elimination half-life.
The elimination half-life is dependent on the clearance and the volume of distribution. The elimination half-life is best determined after intravenous administration. It should be remembered that the half-life is dependent on both the clearance and the volume of distribution. A large volume of distribution results in a long elimination half-life as can be seen for fluticasone propionate (t1/2 = 7–8 hours) (10, 57, 62, 64, 65). Mometasone fuorate also has a long elimination half-life after intravenous administration; it is reported to be 5.8 hours (23). The other corticosteroids have shorter elimination half-lives, reported as 2.8 hours for budesonide (26, 44, 65), 2.0 hours for triamcinolone acetonide (10, 26, 28, 44, 64, 65), and 1.3 hours for flunisolide (10, 27, 44, 64, 65, 68). Daley-Yates and coworkers found a half-life of 0.5 hours and 2.7 hours after intravenous administration for the prodrug beclomethasone dipropionate and its active metabolite 17-beclomethasone monopropionate, respectively (22). Ciclesonide and des-ciclesonide have a reported half-life of 0.36 and 3.4 h, respectively (69).

Terminal half-life after inhalation/intranasal administration.
It is necessary to distinguish between the elimination half-life and the terminal half-life after inhalation, as these can differ. For example, the half-life for fluticasone propionate is between 7 and 8 hours after intravenous administration, but increases to around 14 hours after inhalation of the drug (16, 57, 66). In the latter case, the half-life is no longer determined by clearance and volume of distribution and therefore by the elimination but rather by the absorption. Hence, the slower the terminal elimination half-life, the slower the drug is absorbed and the longer it is retained in the lungs (16, 44). However, Thorsson and colleagues reported the elimination half-life after intravenous administration of fluticasone propionate to be 14.4 hours. They explain the long elimination half-life with an intensive distribution of the drug into the tissue (66). Triamcinolone acetonide and 17-beclomethasone monopropionate show significantly longer terminal half-lives after inhalation than after intravenous administration (16, 24, 28, 44). The longer terminal half-life after inhalation is positively correlated with the pulmonary residence time of the drug in the lung, therefore, increasing the efficacy of the drug. The other corticosteroids, such as beclomethasone dipropionate, budesonide, ciclesonide, and flunisolide have terminal half-life values similar to the elimination half-life (10, 24, 26, 27, 44, 64, 68, 70). Table 1 summarizes the elimination and terminal half-lives for the different corticosteroids.

Hermann and coworkers studied the pharmacokinetics and pharmacodynamics of intranasal administered loteprednol etabonate and fluticasone propionate (71). They found that the terminal half-lives of loteprednol and fluticasone after intranasal administration are around 2 hours and around 4 hours, respectively (66).

Mean Absorption Time
The mean absorption time (MAT) describes the average time it takes for a molecule of a drug to get absorbed into the systemic circulation (65). This parameter can be used to estimate the duration of pulmonary retention for inhaled corticosteroids. A longer retention in the lung leads to a longer availability of the drug in the lung and hence increases the release time, which is positively correlated with an increased local activity. Therefore, a longer MAT indicates a greater pulmonary residence (65). The MATs for fluticasone propionate, triamcinolone acetonide, and budesonide are reported to be 5 to 7 hours (72), 2.9 hours (28), and around 1 hour (72), respectively. The long MAT of fluticasone is in agreement with its relatively low aqueous solubility and might suggest a longer availability of fluticasone in the lungs (72).

Lipid Conjugation
Another way of drug targeting to the lung/nose is the in vivo formation of lipid conjugates. Corticosteroids with a hydroxyl group in the 21-position are able to reversibly bind to fatty acids in the lung and nose, respectively. These lipid conjugates are not absorbed from the lung/nose into the systemic circulation and are not active (73). Moreover, they retain the corticosteroid in the tissue, thus acting as slow release reservoirs. From this depot the drug is gradually released by hydrolysis of the ester bond (16). It should be kept in mind that lipid conjugation and lipophilicity are not the same. Lipid conjugation is a true chemical reaction, producing an ester bond between the corticosteroid and a fatty acid, whereas lipophilicity is a physicochemical characteristic of the compound itself (16). It could be shown in several studies that budesonide is able to form those esters with fatty acids with the help of ATP and acetyl CoA (73–77) (Figure 3). Compared with fluticasone propionate, budesonide is 6 to 8 times less lipophilic, and its receptor binding affinity is also smaller than that of fluticasone propionate (78). However, budesonide seems to be retained in the lung/nose for a longer time due to the highly lipophilic fatty acid esters, which increase the lipophilicity of budesonide 500 to 10,000 times (73, 76, 78). The conjugation of budesonide with fatty acids is rapidly formed in airway and lung tissue. Only 20 minutes after inhalative administration around 80% of budesonide retained in the large airways was found conjugated. No fatty acid conjugates were detected for fluticasone propionate, which is in accordance with its chemical structure (73).



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  		Figure 3. Lipid-conjugate formation of budesonide.

 
The conjugation process is reversible. In several experiments, it could be shown that budesonide conjugates gradually hydrolyze and release free budesonide (73, 75, 76). It seems that budesonide is esterified in most tissues to varying degrees. It could be found that the same fatty acid formation also happens in the nasal mucosa but not in peripheral tissue, prolonging the effect of budesonide in the treatment of allergic rhinitis without increasing the systemic side effects (76).

Des-ciclesonide, the active metabolite of the new corticosteroid ciclesonide, on the other hand has the necessary 21-hydroxyl group and, therefore is able to form fatty acid esters. This will lead to a longer retention time in the lungs, allowing for a longer efficacy. The formation of lipid conjugates has not been related to adverse effects (69).

Although 17-beclomethasone monopropionate, flunisolide, and triamcinolone acetonide have the necessary free 21-hydroxyl group, these corticosteroids have not been shown esterification with fatty acids. The reason for that is not clear, but it could be postulated that the groups at the 16- and 17-position sterically hinder the formation of the lipid conjugate.


   DISCUSSION
TOP
 ABSTRACT
 PHARMACODYNAMIC PROPERTIES
 PHARMACOKINETIC PROPERTIES
 DISCUSSION
REFERENCES
 
The present article reviews the factors affecting efficacy and safety of current corticosteroids and describes the characteristics of an ideal corticosteroid. The ideal corticosteroid will probably never exist, but understanding these issues will guide us in finding a corticosteroid that combines most of the desired characteristics. To be highly effective in the lung or nose, a corticosteroid should have a long pulmonary and nasal retention time, respectively. This can be achieved by either high lipophilicity due to a slow dissolution of the drug in the lung and nose (fluticasone propionate) or by the way of lipid conjugation (budesonide, ciclesonide). Once the drug is absorbed into the systemic circulation it should be highly bound to plasma proteins and be cleared rapidly by the liver, decreasing the possibility of interaction with systemic glucocorticoid receptors. In addition, it should have a low oral bioavailbility and hence limit the systemic availability of swallowed drug. A prodrug or softdrug structure is also beneficial in increasing the local effects and decreasing the unwanted side effects. Administration of the drug directly to the site of action is another important factor for the inhalative therapy. It is dependent on the device used for drug delivery and its formulation. Much progress has been made over the last years to optimize corticosteroid therapy, but there is still room for further improvement.


   FOOTNOTES
 
Conflict of Interest Statement: J.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; G.H. has participated as a speaker in scientific meetings and courses organized by Aventis and Glaxo and received consulting fees from Lilly and AstraZeneca and owns stock in Nanotherapeutics and obtained research grants during the last three years from Sepracor, AstraZeneca, 3M, IVAX, West Pharmaceuticals and is involved in a patent on slow release coatings for pulmonary delivery; H.D. has been a consultant for Altana and Aventis.

(Received in original form March 22, 2004; accepted in final form May 25, 2004)


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 DISCUSSION
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