Pharmacodynamics and pharmacokinetics of inhaled glucocorticoids

Transcription

1 Pharmacodynamics and pharmacokinetics of inhaled glucocorticoids Malcolm Johnson, PhD Middlesex, United Kingdom Research during the past two decades has shown that the inflammatory component of bronchial asthma has a highly complex and multifactorial pathophysiology. Inhaled corticosteroids have become first-line therapy for the treatment of moderate to severe asthma as a result of glucocorticoid action at the cellular level to attenuate the underlying disease processes. This article summarizes the findings of recent studies of the specific pharmacodynamic and pharmacokinetic mechanisms of glucocorticosteroids as a means of classifying individual drugs for use in the management of asthma and other airway diseases. In general, the glucocorticosteroid molecule is required to penetrate the cellular membrane and demonstrate affinity for the steroid-binding site on the glucocorticoid receptor, leading to activation of the receptor. Dimerization of the active steroidreceptor complex occurs, and the complex then enters the nucleus to bind to glucocorticoid responsive elements on a target gene to influence gene transcription and inhibit proinflammatory mechanisms, or to potentiate endogenous antiinflammatory mechanisms. Alternatively, a direct interaction of the glucocorticoid-receptor complex with transcription factors may also be an important determinant of steroid action and a key mechanism whereby glucocorticosteroids exert some of their antiinflammatory activities. 1 PHARMACOKINTICS AT TH TISSU AND CLLULAR LVL Lipophilicity The physicochemical properties of glucocorticoid molecules play a central role in determining pharmacokinetics at the tissue and cellular level. The most From Glaxo Wellcome Research and Development Ltd., Middlesex, United Kingdom. Reprint requests: Malcolm Johnson, PhD, International Medical Affairs, Glaxo Wellcome Research and Development Ltd., Stockley Park West, Uxbridge, Middlesex UBll 1BU, United Kingdom. J ALLRGY CLIN IMMUNOL 1996;97: Copyright 1996 by Mosby-Year Book, Inc /96 $ /0/69841 Abbreviations used BDP: Beclomethasone dipropionate 17-BMP: Beclomethasone-17-monopropionate FP: Fluticasone propionate PFR: Peak expiratory flow rate RBA: Relative receptor-binding affinities RBC: Red blood cells SLPI: Secretory leukocyte protease inhibitor important of these physicochemical properties is lipophilicity, which is an index of the lipid partitioning potential and is inversely related to water solubility. The ranked order of lipophilicity in a series of glucocorticoids currently used to treat bronchial asthma is as follows: fluticasone propionate (FP) > beclomethasone dipropionate (BDP) > budesonide > triamcinolone acetonide > flunisolide, with FP being threefold and 300-fold more lipophilic than BDP and budesonide, respectively. H6gger et al. 2 examined the dissolution rates of the crystalline forms of various glucocorticoids in human bronchial fluid. They demonstrated that flunisolide, the least lipophilic steroid, dissolved most quickly, followed by budesonide (Table I). In sharp contrast, the two highly lipophilic steroids, BDP and FP, dissolved extremely slowly (BDP, >5 hours; FP, >8 hours), in keeping with their low water solubilities (Table I). The findings of H6gger et al. 2 suggest that the more lipophilic corticosteroids may be deposited as "micro-depots" on the airway mucosa, thereby prolonging the duration of action of their local antiinflammatory effects. TISSU UPTAK AND DISTRIBUTION Further potential advantages of increased lipophilicity in a glucocorticoid molecule are (1) increased deposition in lung tissue, (2) consequent slow release from the lung lipid compartment, (3) increased affinity for the glucocorticoid receptor, and (4) prolonged glucocorticoid receptor occupancy. H6gger et al. 2 examined human lung fragments in vitro and observed variations in tissue uptake of 169

2 170 Johnson J ALLRGY CLIN IMMUNOL JANUARY 1996 = 6- ~4- ~a- ~2 35 I- A 7 ~6. =,$ "o.~ 3- {J B i 0 FP 17-BMP ~ Flunisolide BDP Budesonide C) Hydrocortisone 1; ' ~o' ~o ' 20 ' s~ ' do Time (min) T FP Budesonide BDP [] Flunisolide t ' 1~ ' 2'0 3'0 '.'0 ' 5~ ' 60 Time (min) FIG. 1. A, Binding of glucocorticoids to human lung tissue. FP and BDP show the fastest and highest rate of uptake, followed by 17-BMP, budesonide, flunisolide, and hydrocortisone; n = 3. B, Comparative retention of corticosteroids in human lung tissue. FP and BDP, with the highest lipophilicity, show the highest level of tissue retention at equilibrium. (From H6gger P, et al. ur Respir J 1994;584s and H6gger P, et al. ur Respir J 1994;382s.) several corticosteroids. They found that FP and then BDP showed the fastest and highest rate of uptake, followed by beclomethasone-17-monopropionate (17-BMP: the active metabolite of BDP), budesonide, flunisolide, and hydrocortisone (Fig. 1, A). In another study 3 in which the re-equilibration of steroids between lung tissue and plasma was monitored, fluticasone and BDP, which have the highest lipophilicity, showed the highest level of tissue retention at equilibrium, measured as bound T 70 TABL I. Corticosteroid crystal dissolution in human bronchial fluid Flunisolide Budesonide BDP FP Dissolution time <2 min 6 rain >5 hr >8 hr Modified from H6gger P, et al. ur Respir J 1994;584s. glucocorticoid in nanograms per milligram of wetweight tissue (Fig. 1, B), compared with the less lipophilic agents, budesonide and flunisolide. The clinical relevance of these differences has been illustrated by two recent studies. Van den Bosch et al. 4 demonstrated that at 90 minutes after administration of 1.6 mg inhaled budesonide, concentrations in lung tissue were eight times that measured in blood plasma. This ratio was consistent for up to 4 hours after administration of the dose. In a similar experiment conducted by H6gger et al., 5 the distribution of inhaled FP (1 mg) at up to 6.5 hours after administration showed high concentrations in lung tissue and low concentrations in the plasma; indeed, the lung:plasma FP ratios ranged from 70:1 to 165:1 (Table II). Because the studies by Van den Bosch et al. 4 and H6gger et al. 5 are comparable, FP is shown to have a greater than 10-fold higher lung:systemic ratio than budesonide, which is a finding entirely predictable from the relative lipophilicities of the two corticosteroids and from the in vitro tissue uptake/ retention studies (Fig. 1, A and B).2. 3 GLUCOCORTICOID RCPTORS Receptor affinity Data from H6gger and Rohdewald 6 derived from binding studies carried out with isolated glucocorticoid receptors in the cytosolic fraction from human lung tissue show that FP (affinity constant 0.5 nmol/l) has an approximately 20-fold greater glucocorticoid receptor affinity than dexamethasone and a two- and threefold greater glucocorticoid receptor affinity than 17-BMP and budesonide, respectively. Similar data are reported by Derendorf et al. 7 The affinity of a corticosteroid for its receptor may be influenced by several factors, in particular the configuration of the molecule. As Dahlberg et al. 8 illustrate in the case of budesonide, the (22S)- and (22R)-enantiomers have different relative receptor-binding affinities, with budesonide (22R) showing the greatest relative affinity (11.2; dexa-

3 J ALLRGY CLIN IMMUNOL Johnson 171 VOLUM 97, NUMBR 1, PART 2 TABL II. Inhaled fluticasone propionate: lung/systemic distribution Time after inhalation Plasma Lung tissue (min) (pg/ml) (ng/gm) Ratio: lung/ plasma Data from H6gger P, et al. ur Respir J 1995;8:3035. TABL III. Human lung glucocorticoidreceptor complex half-life Steroid-receptor TI/2 (hr) Dexamethasone 1.1 Methylprednisolone 0.5 Triamcinolone BMP 7.5 Flunisolide 3.5 Budesonide 5.1 FP 10.5 Data from H6gger P, Rohdewald P. Steroids 1994;59: and W~rthwein G, et al. Pharm Ztg Wiss 1992;5:2-8. methasone = 1.0), racemic budesonide (22R,22S) having an intermediate affinity at 7.8, and budesonide (22S) having the lowest receptor-binding affinity at 4.2. FP is a single enantiomer, and therefore the observed relative affinity (approximately 20) is the true affinity. Receptor kinetics As shown in Fig. 2 with data derived from H6gger and Rohdewald, 6 glucocorticosteroids are considerably different in terms of their receptor kinetics. In cytosolic fractions of human lung, the rate of association of FP with the steroid receptor was greater (Fig. 2) than that shown by dexamethasone, methylprednisolone, or triamcinolone. 6 In contrast, in terms of the dissociation of the various glucocorticoids from their receptors in the human lung, it is clear that methylprednisolone dissociates very quickly, followed by dexamethasone and triamcinolone. Fluticasone propionate, the most lipophilic steroid, has an extremely slow rate of dissociation. 6 It may be inferred from these data that there will be differences in the stability of the active steroid-receptor complex, which mediates the biologic and therapeutic activity of the glucocorticoid. The data in Table III, which are drawn from several studies, 6, 9, lo indicate the range of values for glucocorticoid-receptor complex stability in human lung tissue as calculated by the half-life (Yl/2 in hours). FP has the greatest receptor-complex stability with a calculated half-life of 10.5 hours, compared with 5.1, 3.5, 7.5, and 3.9 hours for budesonide, flunisolide, 17-BMP, and triamcinolone, respectively. The long half-life of the active FP-receptor complex has important implications for its efficacy as an antiinflammatory agent. PHARMACODYNAMICS OF GLUCOCORTICOIDS Receptor affinity and relative potency When considering the pharmacodynamics of glucocorticoids, it is important to question whether differential data on steroid interactions with isolated receptors are predictive of relative antiinflammatory potency and onset and duration of action in intact target cells in vitro and in vivo in humans. Such a correlation can be drawn from in vitro studies by nglish et al., 11 in which steroid inhibition of the proliferative response of human T-lymphocytes to anti-cd3 was investigated. The potencies of dexamethasone, FP, BDP, and budesonide, measured in terms of the concentration required to elicit 50% inhibition of response (IC5o), were 5.9, 0.3, 2.0, and 0.8 nmol/l, respectively. I~ It is interesting to note that the differences observed in receptor affinities across the same range of steroids 6 mimic these differences in ICs0 values very closely. In addition, Abbinante-Nissen et al. 12 have shown that corticosteroids induce the synthesis of the antiprotease, secretory leukocyte protease inhibitor (SLPI) in human airway epithelial cells. The same study compared the relative potencies of corticosteroids and found that FP was the most potent, increasing SLPI transcript levels by 50% at concentrations as low as 0.1 nmol/l. It is useful to compare the effect of glucocorticoids on SLP112 with the receptor affinity ranking established by Derendorf et al. 7 In effect, there is a good correlation between receptor affinity and the ability of the steroid to induce protease inhibitor (Table IV). 7,12 A similar correlation was observed by Dahlberg et al., s as illustrated in Table V, where relative receptor-binding affinity and relative potency for inhibition of edema were compared.

4 172 Johnson J ALLRGY CLIN IMMUNOL JANUARY Fluticasone propionate ~ Methylprednisolone O Dexamethasone Triamcinolone 0.8-0, I I I I I I I I Time (min) FIG. 2. Glucocorticoid receptor kinetics. Curves demonstrate that in cytosolic fractions of human lung, the rate of association of fluticasone propionate with the steroid receptor is greater than that shown by dexamethasone, methylprednisolone, or triamcinolone. (Data from H6gger P, Rohdewald P. Steroids 1994;59: ) TABL IV. Correlation between receptor affinity and protease inhibitor induction Receptor affinity (so; ng/ml) Protease inhibitor (Cso; nmol/l) Hydrocortisone Dexamethasone Methylprednisolone Triamcinolone FP so, Concentration needed to produce half the maximum effect; Cso, concentration needed to produce and maintain 50% effect. Modified from Derendorf H, Hochhaus G, M6Umann H, et al. Receptor-based pharmacokinetic-pharmacodynamic analysis of corticosteroids. J Clin Pharmacol 1993;33:115-23, Lippincott-Raven Publishers, New York, and Abbinante-Nissen JM, et al. Am J Respir Crit Care Med 1994;149:A869. In vivo studies As documented by Sareen et al. 13 and others, 14,15 the MacKenzie test, in which cutaneous vasoconstriction or "skin blanching" is measured in healthy subjects, has been used to rank the topical antiinflammatory potency of corticosteroids. Fluticasone propionate was the most potent steroid tested, TABL V. Correlation between in vivo activities: receptor-binding affinity and edema inhibition Relative receptorbinding affinity Relative potency: inhibition of edema Dexamethasone Triamcinolone acetonide Budesonide (22R, 22S) 22R-budesonide S-budesonide OH-budesonide c~-hydroxy prednisolone r = Modified from Dahlberg, Thaldn A, Brattsand R, et al. Correlation between chemical structure, receptor binding, and biological activity of some novel, highly active, 16a, 17a-acetalsubstituted glucocorticoids. Mol Pharmacol 1983;25:70-8. being threefold greater than BDP and budesonide and 10-fold greater than triamcinolone and flunisolide. 13 There was again a good correlation between relative receptor affinity 7 and relative skin blanching potency in humans? 3

5 J ALLRGY CLIN IMMUNOL Johnson 173 VOLUM 97, NUMBR 1, PART 2 Morning PFR vening PFR "-" 20- c (1) u) t~ 15-.Q Doubling dose linear trend p=0.001 BDP value m ~'~ 20- t- 0~ u).q Doubling dose linear trend p=0.017 c e- 5- W c x:: 5- W BDP value +1 ~-~ O- e- +l O- e- N -5 I I I I ~ -5 I I I I Fluticasone propionate Fluticasone propionate (lag/day) (lxg/day) FIG. 3. Demonstration of dose response to fluticasone propionate over the dose range on both morning and evening PFR. Standard comparison dose of BDP, 400 i~g/day, was used (dashed lines). Curves show that fluticasone propionate, 200 ixg/day, had an effect on morning PFR and evening PFR equivalent to that of BDP, 400 t~g/day. (From Dahl R, Lundback B, Malo JR, et al. A dose-ranging study of fluticasone propionate in adult patients with moderate asthma. Chest 1993;104: ) Clinical studies In a recent clinical study 16 in which increasing doses of FP (100 to 800 Ixg/day) were administered twice daily for 4 weeks, the relative effects of the steroid on morning peak expiratory flow rate (PFR) and evening PFR were monitored. As can be seen in Fig. 3, there is a dose response to FP over the dose range on both morning and evening PFR. In the same study, a standard 400 txg per day dose of BDP was included to compare the relative efficacy of BDP with that of FP. It was shown that FP, 200 txg per day, had an effect on morning and evening PFR equivalent to BDP administered at 400 ~xg per day (see dashed lines in Fig. 3). It may be inferred from these data that there is a 2:1 ratio in corticosteroid potency between FP and BDP. 16 Similar findings have been reported by Ayres et al., 17 who showed that 1 and 2 mg of FP had higher clinical efficacy than budesonide at 1.6 mg. These clinical findings are as would be predicted from a two- to threefold higher receptor affinity for FP compared with 17-BMP, the active metabolite of BDP, and budesonide. 6 In an extended clinical study of 274 patients who received either FP, 1.5 mg per day, or BDP, 1.5 mg per day, and who were followed-up for 1 year, 18 a faster onset of response in terms of improvement in morning PFR was observed with FP compared with BDP (Fig. 4). It is interesting to speculate that this fast onset may reflect the rapid rate of association of FP with the glucocorticoid receptor shown in Fig. 2. It therefore appears that the receptor pharmacokinetics of glucocorticoids are indeed predictive of their pharmacodynamics, both in vitro in intact target cells and in vivo in healthy subjects and in patients with bronchial asthma. PHARMACOKINTICS OF INHALD CORTICOSTROIDS When any drug is properly inhaled, approximately 20% of the dose is deposited in the lung and about 80% is swallowed. 19 If the latter portion is absorbed by the gastrointestinal tract, the drug may then undergo first-pass metabolism in the liver to a range of metabolites. If absorbed through the lung, the drug will also in time be metabolized either by the liver or by other extrapulmonary tissues or in the plasma. It is apparent from data compiled by Brattsand and Selroos 2 and others that when comparing the

6 174 Johnson J ALLRGY CLtN IMMUNOL JANUARY 1996 Treatment 40 FP 750~g twice daily (n=133), BDP 750~g twice daily (n=130) ] FIG. 4. Increase in morning PF from baseline; BDP, 750 I~g twice daily (n = 130), compared with fluticasone propionate, 750 ~g twice daily (n = 133). Patients were followed-up for 1 year. Curves demonstrate a faster onset of response with fluticasone propionate compared with BDP. (Modified from Fabbri L, et al. Thorax 1993;48: ) Day TABL Vl. Corticosteroid pharmacokinetics TABL VII. Corticosteroid bioavailability Volume Oral Inhaled Clearance distribution Half-life (%) (%) (L/min) (L/kg) (hr) BDP <20 ~20 Flunisolide Triamcinolone Triamcinolone Budesonide acetonide FP < Budesonide FP Modified from Brattsand B, Selroos O. Current drugs for respiratory diseases. In: Page CP, Metzger WJ, eds. Drugs and the lung. New York: Raven Press, 1994: Intranasal (%) half-life with increased lipophilicity. However, the rates of clearance of the glucocorticoids are similar (Table VI). pharmacokinetic characteristics of inhaled corticosteroids such as clearance (L/min), volume of distribution (L/kg), half-life (hours), and oral bioavailability (%), these drugs may be clearly distinguished from each other. For example, steroids that are slightly lipophilic, such as flunisolide and triamcinolone, have volumes of distribution that are lower than steroids having higher lipophilicity, such as budesonide and FP (Table VI). In addition, there is a corresponding prolongation in Bioavailability There are marked differences in the systemic bioavailability of glucocorticoids. When administered by the oral route, the bioavailability of BDP, flunisolide, triamcinolone, and budesonide has been reported by Brattsand and Selroos 2 as less than 20%, 21%, 22.5%, and 11%, respectively. In contrast, the oral bioavailability of FP has been measured in several studies and found to be less than 1% 21 (Table VII). It has been suggested 2 that

7 J ALLRGY CLIN tmmunol Johnson 175 VOLUM 97, NUMBR 1, PART 2 these values for FP may be low because of binding to red blood cells (RBCs); however, FP RBC binding is rather weak, variable, and completely reversible. There is no indication that RBC binding has any significant influence on values of oral bioavailability of corticosteroids. In contrast to marked differences in oral bioavailability, all glucocorticoids, when administered by the inhaled route, are equally absorbed from the lung. The data in Table VII indicate that this absorption is complete and therefore represents approximately 20% of the administered dose. Few studies have investigated the systemic bioavailability of glucocorticoids given intranasally for allergic rhinitis. The available data indicate 100% bioavailability for budesonide 22 and 1.8% for FP. 23 Metabolism BDP. Rohdewald and Rehder, 24 in a study of BDP and its metabolites, determined that after administration of a 2 mg inhaled dose, plasma levels of beclomethasone were not detectable and levels of BDP were very low (<0.5 ng/ml). In contrast, the active metabolite 17-BMP reached significant plasma levels of 1.8 to 2.5 ng/ml. Budesonide. The metabolites of inhaled budesonide are 6-hydroxy-budesonide and 16-o~-hydroxyprednisoloneY Fluticasone propionate. When metabolized, FP generates a single metabolite in humans, the carboxylic acid. 26 The potential systemic activity of drug metabolites may be assessed with use of steroid receptorbinding affinity as an index. By comparing relative receptor-binding affinities (RBAs), where dexamethasone is assigned an RBA of 1.0, s it is evident that BDP (RBA = 3.2) becomes much more active when metabolized to 17-BMP, which has an RBA of In contrast, budesonide, with an RBA of 7.8, undergoes a marked reduction in binding affinity when metabolized to either 6-hydroxybudesonide (RBA = 0.06) or 16-o~-hydroxy-prednisolone (RBA = 0.03). The 1713-carboxylic acid metabolite of FP has negligible pharmacologic activity (RBA <0.01) compared with the parent molecule (RBA = 18.8). Systemic bioavailability and safety issues As noted earlier, there are marked differences in the overall systemic bioavailability of inhaled corticosteroids, which results from a combination of the oral (swallowed fraction) and lung components. Of primary concern to the clinician is whether an inhaled corticosteroid can exert its desired topical antiinflammatory effects in the lung with little or no systemic activity, particularly suppression of the hypothalamic-pituitary-adrenal axis. Generally speaking, cortisol is the systemic marker used most commonly to monitor effects on the hypothalamic-pituitary-adrenal axis in humans, with a reported relative potency four times higher than the bone marker serum osteocalcin and 10 times that of plasma glucose. 2 Plasma cortisol, urinary cortisol, and responses to synthetic adrenocorticotropic hormone (e.g., cosyntropin) have been used as endpoints in the safety evaluation of inhaled glucocorticoids. Although statistical changes in cortisol have been reported after the administration of high doses, in relatively few cases have plasma levels fallen outside the normal range, and few patients have failed to show an adequate physiologic response to synthetic adrenocorticotropic hormone challenge. The value of cortisol as a marker of systemic activity of glucocorticoids therefore remains unclear. Alternative markers such as bone markers, lower leg length, and bone density have also been proposed and are the subject of ongoing clinical research. However, these studies are by nature of long duration (1 to 2 years), and early assessment of the safety of a newly introduced glucocorticoid will be difficult. It may be possible in the interim to develop surrogate endpoints, such as the relationship between peak plasma levels and the corresponding steroid receptor affinity. For example, peak plasma levels of budesonide after a 1 mg inhaled dose were 1.7 ng/ml? The receptor affinity of budesonide is threefold lower, at 0.65 ng/ml. 6 The corresponding data for FP are 0.3 ng/m121 and 0.25 ng/ml. 6 The predictive potential of these types of relationships, however, remains to be determined. TH FUTUR The introduction of safe and effective inhaled corticosteroids during the past decade signals that clear advances have been made from investigator's bench to patient's bedside. The newer inhaled corticosteroids are more airway selective, have low oral bioavailability, and have increased uptake for and retention in lung tissue. These steroids also have greater receptor affinity and increased intrinsic steroid potency, thus allowing optimal clinical effect to be achieved with low doses. In the context of further advances in inhaled corticosteroids, there are hopes for future targeting of steroids to particular tissues, possibly by utilizing tissue-specific metabolism. In addition, it is perhaps not an unrealizable goal to design a

8 176 Johnson J ALLRGY CLIN IMMUNOL JANUARY 1996 molecule that would have cellular or even genomic specificity. RFRNCS 1. Barnes P J, Adcock IM. Anti-inflammatory actions of steroids: molecular mechanism. Trends Pharmacol Sci 1993; 14: H6gger P, Rawert L, Rohdewald P. Dissolution tissue binding and kinetics of receptor binding of inhaled glucocorticoids [Abstract P1864]. ur Resp J 1993;6:584S. 3. H6gger P, Bonsmann U, Rohdewald P. tttux of glucocorticoids from human lung tissue to human plasma in vitro [Abstract P1735]. ur Respir J 1994;7:382s. 4. Van den Bosch JMM, Westermann CJJ, Aumann J, et al. Relationship between lung tissue and blood plasma concentrations of inhaled budesonide. Biopharm Drug Dispos 1993;14: Hfgger P, smailpour N, Rabe K, et al. Distribution of inhaled fluticasone propionate between lung tissue and blood plasma in vivo [Abstract P1530]. ur Respir J 1995;8: H~Sgger P, Rohdewald P. Binding kinetics of fluticasone propionate to the human glucocorticoid receptor. Steroids 1994;59: Derendorf H, Hochhaus G, M611mann H, et al. Receptorbased pharmacokinetic-pharmacodynamic analysis of corticosteroids. J Clin Pharmacol 1993;33: Dahlberg, Thal6n A, Brattsand R, et al. Correlation between chemical structure, receptor binding, and biological activity of some novel, highly active, 16a, 17aacetal-substituted glucocorticoids. Mol Pharmacol 1983; 25: Wiirthwein G, Rehder S, Rohdewald P. Lipophilie und Rezeptoratfinitfit von Glucocorticoiden. Pharm Ztg Wiss 1992;5: Rohdewald P, M611mann HW, Hochhaus G. Atfinities of glucocorticoids for glucocorticoid receptors in the human lung. Agents Actions 1985;17: nglish AF, Neate MS, Quint DJ, Sareen M. Biological activities of some corticosteroids used in asthma [Abstract]. Am J Respir Crit Care Med 1994;149:A Abbinante-Nissen JM, Simpson LG, Leikauf GD. Corticosteroids increase secretory leukocyte protease inhibitor transcript levels in airway epithelial cells [Abstract]. Am J Respir Crit Care Med 1994;149:A Sareen M, et al. Comparative topical potencies of corticosteroids. ur Respir J (in press). 14. Brattsand R, Thal6n A, Roempke K, et al. Development of new glucocorticoids with a very high ratio between topical and systemic activities. ur J Respir Dis 1982;63(suppl): Johansson SA, Andersson K, Brattsand R, et al. Topical and systemic glucocorticoid potencies of budesonide, beclomethasone dipropionate and prednisolone in man. ur J Respir Dis 1982;63(Suppl): Dahl R, Lundback B, Malo JR, et al. A dose-ranging study of fluticasone propionate in adult patients with moderate asthma. Chest 1993;104: Ayres JG, Bateman D, Lundback B, Harris TAJ. Highdose fluticasone propionate, 1 mg daily, versus fluticasone propionate, 2 mg daily, or budesonide, 1.6 mg daily, in patients with chronic severe asthma. ur J Respir Dis 1995;8: Fabbri L, Burge PS, Croonenborgh L, et al. Comparison of fluticasone propionate with beclomethasone dipropionate in moderate to severe asthma treated for one year. Thorax 1993;48: Barnes PJ. Inhaled glucocorticoids for asthma. N ngl J Med 1995;332: Brattsand R, Selroos O. Current drugs for respiratory diseases. In: Page CP, Metzger WJ, eds. Drugs and the lung. New York: Raven Press, 1994: Holliday SM, Faulds D, Sorkin M, et al. Inhaled fluticasone propionate: a review of its pharmacokinetic properties and therapeutic use in asthma. Drugs 1994;47: dsbacker S, Andersson K, Ryrfeldt A. Nasal bioavailability and systemic effects of the glucocorticoid budesonide in man. ur J Clin Pharmacol 1985;29: McDowall J, Mackie A, Bye A, Ventresca GP. Very low systemic exposure to intranasal fluticasone propionate [Abstract]. J ALLRGY CLIN IMMUNOL 1995;95: Rohdewald P, Rehder S. Plasma levels of bectomethasone dipropionate (BDP) and its 17-monopropionate metabolite (17-BMP) following BDP inhalation [Abstract P1733]. ur Respir J 1994;7:382S. 25. Phillipps GH. Structure-activity relationships of topically active steroids: the selection of fluticasone propionate. Respir Med 1990;84(suppl A): Brattsand R, Axelsson B. New inhaled glucocorticoids. In: Barnes PH, ed. New drugs for asthma; vol. 2. London: IBC Technical Services Ltd., 1992: