Professional Documents
Culture Documents
Comparative Pharmacology, Bioavailability, Pharmacokinetics, and Pharmacodynamics of Inhaled Glucocorticosteroids
Comparative Pharmacology, Bioavailability, Pharmacokinetics, and Pharmacodynamics of Inhaled Glucocorticosteroids
Comparative Pharmacology, Bioavailability, Pharmacokinetics, and Pharmacodynamics of Inhaled Glucocorticosteroids
* Corresponding author.
E-mail address: hartmut@cop.ufl.edu (H. Derendorf).
0889-8561/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.iac.2005.05.004 immunology.theclinics.com
470 hÜbner et al
F
O
O O
F
Triamcinolone acetonide Budesonide Flunisolide
O
CH 2OH S CH22 F
CH2 O C CH22 CH33
O O O C O
O C O HO OCC CH22 CH33
O
HO O
CH33
hÜbner et al
HO O CC
C CH H22 CH33 CH3 O
CH33
Cl F
Cl O O
O F
Beclomethasone Mometasone furoate Fluticasone propionate
dipropionate
O
O
O
HO O H
Ciclesonide
Fig. 2. Structures of the seven inhaled corticosteroids that are available on the market.
inhaled glucocorticosteroids 473
The fate of an inhaled glucocorticoid relates the safety concerns about the
use of these agents to the route the drugs are taking in the body. The deposition of
the drug in the body compartments depends on the agent and its inhalation
device. Approximately 10% to 60% of the administered inhaled corticosteroid is
deposited in the lungs. The pulmonary deposition percentages of different
inhalers are as follows [13–16]:
MDI: 10%–15%
Diskus DPI: 14%–20%
Diskhaler: 10%–15%
MDI with spacer: 15%–25%
Turbohaler: 20%–30%
HFA-MDI: 60%
In the lungs the agent exerts an effect on the inflamed tissue as soon as it is
dissolved into the pulmonary lining fluid to enter the cells and bind to the
intracellular receptor. In some cases the agent is not active in its native form and
has to become activated first to express an effect (prodrug concept). Over time
the drug gets absorbed and reaches the systemic circulation and adverse effects
can occur.
Additionally, the rest of the drug that did not get deposited in the lung
(40%–90%) may reach the systemic circulation after its deposition in the mouth
and pharynx. From there it gets swallowed and reaches the gastrointestinal (GI)
tract. When the drug stays a prolonged time in the intestine, there is an increased
risk for the drug to be absorbed into the systemic circulation. Fortunately, first-
pass metabolism in the liver inactivates most of the drug and only a small part
of it is orally bioavailable. The bioavailable fraction can lead to serious adverse
effects as soon as it reaches the corticosteroid receptors of the different body
compartments, but it also diffuses back to the lungs to be absorbed and occupy
the pulmonary anti-inflammatory corticosteroid receptors.
Pharmacodynamics
serious adverse effects in other parts of the body. Serious local and systemic
adverse effects are associated with the chronic use of inhaled corticosteroids.
Local adverse effects such as oral candidiasis, hoarseness, and throat infections
are possible. Osteoporosis, growth retardation in pediatric patients, ophthalmo-
logic effects, and adrenal suppression are some of the systemic adverse effects
that can occur during the chronic use of inhaled corticosteroids [18]. Receptor
potency is a pharmacodynamic parameter that is used to evaluate the relationship
between drug concentration and development of an effect.
Receptor potency
extent. Therefore, the synthesis of proteins that again induce the formation of
adverse effects is reduced [28,29]. This observation may be useful to achieve a
better pharmacodynamic profile for inhaled corticosteroids. High lung selectivity
could be achieved for those inhaled corticosteroids that express a higher se-
lectivity for the transrepression pathway. Further studies are necessary to confirm
this observation that may be useful to develop safer inhaled corticosteroids.
Animal models and in vitro models have evaluated the selectivity profile for the
newer glucocorticoids, but for now studies do not show a beneficial clinical effect
that assesses the transrepression and transactivation potencies [30,31].
Prodrug design
Beclomethasone dipropionate and ciclesonide are the two agents that can
be distinguished from the other inhaled glucocorticosteroids because they are
prodrugs. These drugs are not active in their native form; they need to be
activated by metabolic reaction. One big advantage of prodrugs can be the
minimization of oropharyngeal adverse effects because the parent compound that
is inhaled through an inhalation device is not pharmacologically active. When
deposited in the oropharynx it does not exert the same effect as the other active
inhaled corticosteroids. Ciclesonide is metabolized to des-CIC through cytosolic
esterases in the airways (Fig. 3) [32,33]. After inhalation it could be shown that
only little activated des-CIC could be recovered from a mouth wash in
comparison to fluticasone propionate [34].
Although it still has to be clarified if other big advantages of prodrugs exist
besides their decreased risk for oropharyngeal adverse effects, it could be
assumed that they have a better pulmonary targeting because of the activation of
the prodrug in the lungs.
However, there is no evidence that the activation specifically occurs in the
lungs. The prodrugs can also be cleaved by esterases outside of the pulmonary
tissue, which could lead to an increased systemic bioavailability of the active
O CH33
CH
CH
CH22 O CCC CH
H CH2 OH
O C CH3 O C
3
HO
HO O HH HO O H
C
O O C
O O
Ciclesonide des-Ciclesonide
parent compound active principle
Oral bioavailability
One parameter that has a high impact on the safety of inhaled corticosteroids
is the bioavailability, because the systemic availability correlates with its rate of
adverse effects. It is necessary to distinguish between oral and pulmonary
bioavailability [19,35]. The pulmonary bioavailability of an inhaled cortico-
steroid is the rate and extent at which the drug reaches its site of action, and the
systemic bioavailability shows the rate and extent of the drug that reaches the
blood. The sum of pulmonary and oral fraction absorbed represents the systemic
concentration that can lead to systemic adverse effects. A high pulmonary
bioavailability and a low oral bioavailability are desired. Oral bioavailability
depends on the delivery device that is used. Oral bioavailability can be deter-
mined by measuring the plasma levels or the amount of drug excreted in urine
over a specific period. Charcoal is used to prevent the absorption of the glu-
cocorticoid from the GI tract. The difference between the drug absorption after
application of inhaled corticosteroids alone and with concomitant charcoal block
reflects oral absorption. Ryrfeldt and colleagues [36] report the oral bioavail-
ability of budesonide to be 11%. In comparison, the study of Thorsson and
colleagues [14] determined that 32% of inhaled budesonide was absorbed without
charcoal and 18% of the dose was absorbed with charcoal. The difference of
14% is similar to the result of 11% that is obtained when oral and intravenous
dosing are compared. Belomethasone-17-monopropionate has a high oral bio-
availability of 26% [12,37]. Flunisolide exhibits an oral bioavailability of 7%
[37]. Fluticasone propionate and ciclesonide have negligible oral bioavailabilities
of less than 1% [38–40].
There are conflicting studies reported about the oral bioavailability of
mometasone furoate. One single-dose study reported an oral bioavailability of
less than 1% [41]. However, after multiple dose administration a systemic bio-
availability of 11% was measured [42].
The oral bioavailability of inhaled corticosteroids has to be small if the
oropharyngeal deposition is high to ensure that enough drug reaches the lungs to
maintain a high pulmonary selectivity.
inhaled glucocorticosteroids 477
Clearance
CL ¼ Dose=AUC
It quantifies the volume of body fluid (eg, plasma) that is cleared per time
unit (L/h, mL/min). If there is no saturation of elimination, a clearance is usually
constant and independent of drug concentration. To evaluate the clearance of
an inhaled corticosteroid, its value can be related to the liver blood flow of
approximately 90 L/h [35]. When the liver rapidly metabolizes the compound, it
can be expected that the drug will have a clearance similar to the hepatic blood
flow. The maximum rate of elimination for hepatically metabolized drugs would
be achieved [22]. The clearance for the most inhaled corticosteroids illustrates
that it is similar to the hepatic blood flow. Beclomethasone-17-monopropionate,
budesonide, and fluticasone propionate have a clearance of 120 L/h [12], 84 L/h
[15,36], and 69 L/h [15], respectively. The metabolites of the drugs that are
administered as inactive parent compounds, such as beclomethasone-17-
monopropionate and des-CIC, have apparent clearance values (CL/F, where F
is the fraction of the parent compound converted to the active metabolite). It is
assumed that the parent compound is completely metabolized to the active
metabolite and that no other metabolism takes place. It is shown that ciclesonide
gets converted to des-CIC in the lungs [33,43]. For des-CIC, the apparent
clearance is reported to be 228 L/h [40,44]. The apparent clearance of des-CIC is
measured after administration of the active principle and does not reflect the real
clearance values after administration of the parent compound. The high clearance
values show that clearance is not only dependent on the hepatic blood flow
but also that extrahepatic clearance has an influence on the elimination of the
drug. New drug developments are working on the development of inhaled
corticosteroids that introduce the extrahepatic clearance to minimize systemic
adverse effects and to increase the pulmonary targeting. Metabolic inactivation of
the corticosteroids in the blood could be a tool to further increase the efficacy–
safety profile [5], but it is difficult to design a drug that is efficiently inactivated
in the blood and at the same time has a sufficient stability in the lungs [24].
Because all of the inhaled corticosteroids have a rapid hepatic clearance, there
can be only improvements in drug developments that introduce extrahepatic
clearance properties.
Lung deposition
Lung deposition shows the amount of drug that goes to the lung and there-
fore explains the quantity that exerts an effect at the site of inflammation. With
478 hÜbner et al
51 52
50
Lung deposition in %
39
40
30 28
22
20 16
10
0
BDP FLU BUD TAA FP CIC
different inhaled corticosteroids
Fig. 4. Lung deposition of different inhaled corticosteroids, that are given by way of HFA-MDI.
BDP, beclomethasone dipropionate; BUD, budesonide (p-HFA-MDI); CIC, ciclesonide (HFA-MDI);
FLU, flunisolide; FP, fluticasone propionate (HFA-MDI); TAA, triamcinolone acetonide. (Data from
Refs. [14,16,35,48,71]).
inhaled glucocorticosteroids 479
Lung deposition is also highly dependent on the patients. The lung anat-
omy, the breathing pattern, the disease state, the inhalation technique, and
the mucociliary transport are highly variable between patients. Thus, a good
assessment of the patient is the right way to prevent a wrong treatment of the
disease. Studies using gamma scintigraphy were used to evaluate patient training
and the effect of disease. As soon as the patient gets trained in the right usage
of the device, a higher lung deposition can be seen through scintigraphy.
Furthermore, healthy volunteers can inspire the drug more efficiently [49]. The
plasma concentration curves in a moderate asthmatic and a healthy volunteer who
were both using fluticasone propionate through MDI are significantly different.
The levels in healthy subjects are almost twice as high.
Inhaler device
There are different inhalers available on the market. The devices that are
used primarily are pressured MDIs (p-MDIs) and dry powder inhalers (DPI).
Nebulizers are mainly used in children. MDIs are propellant-based and contain
surfactant and lubricants. The newer MDIs use hydrofluoroalkane propellants
(HFA) as their vehicle and the drug is dissolved or suspended in a solution. There
are still some chlorofluorocarbon (CFC)-based MDI suspensions available on the
market, but because of environmental concerns they will be replaced by the HFA
solutions. To use the device, coordination is necessary. The patients must be
assessed for proper technique to ensure they get the desired dose. DPIs are non–
propellant-based and contain solid particles. The patient controls the inhalation
although lung function might affect deposition [12,46,50–53]. However, they
may contain lactose, which is of concern in patients who have lactose intolerance.
A comparison of budesonide DPI and MDI devices showed the following
deposition: DPI deposition was 38%, with 32% of the budesonide dose deposited
in the lung and 6% in the GI tract, whereas the MDI showed a lung deposition of
15% and a GI tract deposition of 11% (see list above) [14]. As long as the device
is used correctly, the inhaler type is not the main factor that influences lung
deposition [14,54]. The size of the particles and the aerosol vehicle for the MDIs
is of more relevance for the determination of lung deposition.
HFA solutions deliver the drug deep into the lungs; they contain a larger
portion of small particles in the aerosol [55]. Leach and colleagues [56] compared
two beclomethasone formulations: a CFC suspension and an HFA solution. The
HFA-134a showed a much better lung deposition of 55% to 60%, whereas the
CFC preparation was mainly deposited in the oropharynx (90%–94%). The HFA
solution contains much smaller particles (1–2 mm versus 2–5 mm) because the
drug gets dissolved in the solution and the distribution throughout the lungs is
more diffuse than with the CFC suspension. The change to the HFA-based
formulations was not easy; the CFC suspensions were already established in the
market and the lower pulmonary deposition of the CFC-MDI resulted in many
challenges because there is no dose equivalence between CFC and HFA products.
480 hÜbner et al
Particle size
The particle size of the dry powder or aerosol droplets is most effective in a
range of 1 to 5 mm median aerodynamic diameter [57]. Particles larger than 5 mm
are deposited in the mouth and trachea, where they may cause local adverse
effects. The larger particles that are of low density and porous can still pass the
trachea and be deposited in bronchi and bronchioles. If the particles are too small,
they pass into the lungs but they will be exhaled immediately. However, ultrafine
particles (b 0.3 mm) may be of interest because they can penetrate into small
airways that have an internal diameter of less than 2 mm.
Protein binding
Protein binding is highly relevant because only the unbound free drug can
exert an effect at the receptor side. As long as the corticosteroid is bound to a
protein, it is unable to bind to any corticosteroid receptor. Albumin is the major
protein involved in protein binding with inhaled corticosteroids. Protein binding
is seen as a storage form of the drug because it is reversible and a rapid equi-
librium is established. High protein binding can be advantageous because the
protein binding decreases the free unbound fraction in the systemic circulation
and therefore the risk for a systemic adverse effect is also decreased. Protein
binding has been reported to be 80% for flunisolide, 87% for beclomethasone
dipropionate, 88% for budesonide, 71% for triamcinolone acetonide, and 90% for
fluticasone propionate [19,22,36,58]. Fig. 5 shows the protein binding of
ciclesonide and its active compound to be 99% [23]. With an increase in protein
binding, the systemic bioavailability of the drug is assumed to be decreased, as
seen with ciclesonide and mometasone furoate. This decrease can lead to a better
risk/benefit ratio because the risk for systemic adverse effects is decreased.
Protein binding can have an effect on the clearance of some drugs, but
that is not the case for inhaled corticosteroids. Inhaled corticosteroids are ‘‘high
extraction drugs,’’ which means they have a high metabolic activity and a high
hepatic clearance, and therefore the protein binding does not limit clearance and
a change in protein binding does not alter the clearance.
Newer compounds show an improvement in protein binding. The drugs
become more and more bound to the plasma proteins and it is assumed that less
inhaled glucocorticosteroids 481
120
99 99
100
Protein binding (%)
87 88 90
80
80 71
60
40
20
0
BDP FLU BUD TAA FP CIC des-CIC
Inhaled Corticosteroids
free drug concentration will lead to fewer systemic adverse effects. The increased
protein binding seems to be another property that can influence the development
of safer inhaled corticosteroids.
Volume of distribution
Half-life
t1=2 ¼ ð0:693 Vd Þ=CL; where t1=2 is the half -lif e and Vd is the
volume of distribution
Summary
References
[1] National Center for Health Statistics. FASTSTATS—asthma. Available at: http://www.cdc.gov/
nchs/faststats/asthma.htm. Accessed June 24, 2005.
[2] Norbiato G, Bevilacqua M, Vago T, et al. Glucocorticoids and Th-1, Th-2 type cytokines
inhaled glucocorticosteroids 485
in rheumatoid arthritis, osteoarthritis, asthma, atopic dermatitis and AIDS. Clin Exp Rheumatol
1997;15(3):315 – 23.
[3] Adcock IM, Ito K. Molecular mechanisms of corticosteroid actions. Monaldi Arch Chest Dis
2000;55(3):256 – 66.
[4] Tashkin DP. The role of small airway inflammation in asthma. Allergy Asthma Proc 2002;
23(4):233 – 42.
[5] Tayab Z, Hochhaus G. PK/PD evaluation of inhalation drugs: application to targeted pulmonary
delivery systems. Expert Opinion Drug Delivery 2005;2(3):519 – 32.
[6] Kharitonov S, Alving K, Barnes PJ. Exhaled and nasal nitric oxide measurements: rec-
ommendations. The European Respiratory Society Task Force. Eur Respir J 1997;10(7):
1683 – 93.
[7] Juniper EF, Guyatt GH, Cox FM, et al. Development and validation of the Mini Asthma Quality
of Life Questionnaire. Eur Respir J 1999;14(1):32 – 8.
[8] National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for
the Diagnosis and Management of Asthma Update on Selected Topics–2002. J Allergy Clin
Immunol 2002;110(5 Suppl):S141–219.
[9] Wilson AM, Lipworth BJ. Dose-response evaluation of the therapeutic index for inhaled
budesonide in patients with mild-to-moderate asthma. Am J Med 2000;108(4):269 – 75.
[10] Allen DB, Bielory L, Derendorf H, et al. Inhaled corticosteroids: past lessons and future issues.
J Allergy Clin Immunol 2003;112(3 Suppl):S1–40.
[11] Dietzel K, Engelstatter R, Keller A, et al. Ciclesonide: an on-site activated steroid. In: Hansel T,
Barnes P, editors. New drugs for asthma, allergy and COPD. Basel, Switzerland7 Karger; 2001.
p. 91 – 3.
[12] Daley-Yates PT, Price AC, Sisson JR, et al. Beclomethasone dipropionate: absolute bio-
availability, pharmacokinetics and metabolism following intravenous, oral, intranasal and in-
haled administration in man. Br J Clin Pharmacol 2001;51(5):400 – 9.
[13] Vanden Burgt JA, Busse WW, Martin RJ, et al. Efficacy and safety overview of a new inhaled
corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in
asthma. J Allergy Clin Immunol 2000;106(6):1209 – 26.
[14] Thorsson L, Edsbacker S, Conradson TB. Lung deposition of budesonide from Turbuhaler is
twice that from a pressurized metered-dose inhaler P-MDI. Eur Respir J 1994;7(10):1839 – 44.
[15] Mackie AE, McDowall JE, Ventresca P, et al. Systemic exposure to fluticasone propionate
administered via metered-dose inhaler containing chlorofluorocarbon or hydrofluoroalkane
propellant. Clin Pharmacokinet 2000;39(Suppl 1):17 – 22.
[16] Leach CL, Davidson PJ, Hasselquist BE, et al. Lung deposition of hydrofluoroalkane-134a
beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon
beclomethasone: a cross-over study in healthy volunteers. Chest 2002;122(2):510 – 6.
[17] Buttgereit F, Scheffold A. Rapid glucocorticoid effects on immune cells. Steroids 2002;67(6):
529 – 34.
[18] Toogood JH. Side effects of inhaled corticosteroids. J Allergy Clin Immunol 1998;102(5):
705 – 13.
[19] Derendorf H. Pharmacokinetic and pharmacodynamic properties of inhaled corticosteroids in
relation to efficacy and safety. Respir Med 1997;91(Suppl A):22 – 8.
[20] Boobis AR. Comparative physicochemical and pharmacokinetic profiles of inhaled beclo-
methasone dipropionate and budesonide. Respir Med 1998;92(Suppl B):2 – 6.
[21] Kelly HW. Comparative potency and clinical efficacy of inhaled corticosteroids. Respir Care
Clin N Am 1999;5(4):537 – 53.
[22] Derendorf H, Hochhaus G, Meibohm B, et al. Pharmacokinetics and pharmacodynamics of
inhaled corticosteroids. J Allergy Clin Immunol 1998;101(4 Pt 2):S440–6.
[23] Rohatagi S, Arya V, Zech K, et al. Population pharmacokinetics and pharmacodynamics of
ciclesonide. J Clin Pharmacol 2003;43(4):365 – 78.
[24] Hochhaus G. New developments in corticosteroids. Proc Am Thorac Soc 2004:1;269–74.
[25] Adcock IM, Nasuhara Y, Stevens DA, et al. Ligand-induced differentiation of glucocorticoid
486 hÜbner et al
ciclesonide. The 60th Annual Meeting of the American Academy of Allegy, Asthma and
Immunology, Denver, CO 2003.
[45] Colice GL. Categorizing asthma severity and monitoring control of chronic asthma. Curr Opin
Pulm Med 2002;8(1):4 – 8.
[46] Davies R. Improvements in delivery with an extra fine beclomethasone aerosol. Int J Clin Pract
Suppl 1998;96:28 – 32.
[47] Bethke TD, Boudreau RJ, Hasselquist BE, et al. High lung deposition of ciclesonide in
2D and 3D imaging. Presented at the European Respiratory Society Annual Meeting. Stock-
holm, 2002.
[48] Derendorf H, Pedersen S. Choosing an inhaled corticosteroid for once-daily administration in
asthma. Resp Dig 2004;6(2):1 – 11.
[49] Brutsche MH, Brutsche IC, Munawar M, et al. Comparison of pharmacokinetics and systemic
effects of inhaled fluticasone propionate in patients with asthma and healthy volunteers:
a randomised crossover study. Lancet 2000;356(9229):556 – 61.
[50] Coursin DB, Wood KE. Corticosteroid supplementation for adrenal insufficiency. JAMA
2002;287(2):236 – 40.
[51] Farmer IS, Middle M, Savic J, et al. Therapeutic equivalence of inhaled beclomethasone
dipropionate with CFC and non-CFC (HFA 134a) propellants both delivered via the Easibreathe
inhaler for the treatment of paediatric asthma. Respir Med 2000;94(1):57 – 63.
[52] Davies R, Leach C, Lipworth B, et al. Asthma management with HFA-BDP (Qvar). Hosp Med
1999;60(4):263 – 70.
[53] Davies RJ, Stampone P, O’Connor BJ. Hydrofluoroalkane-134a beclomethasone dipropionate
extrafine aerosol provides equivalent asthma control to chlorofluorocarbon beclomethasone
dipropionate at approximately half the total daily dose. Respir Med 1998;92(Suppl A):23 – 31.
[54] Brocklebank D, Wright J, Cates C. Systematic review of clinical effectiveness of pressurised
metered dose inhalers versus other hand held inhaler devices for delivering corticosteroids in
asthma. BMJ 2001;323(7318):896 – 900.
[55] Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids: lessons for the new
millennium. Drug Saf 2000;23(1):11 – 33.
[56] Leach CL, Davidson PJ, Boudreau RJ. Improved airway targeting with the CFC-free HFA-
beclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J
1998;12(6):1346 – 53.
[57] Howarth PH. Why particle size should affect clinical response to inhaled therapy. J Aerosol
Med 2001;14(Suppl 1):S27–34.
[58] Szefler SJ. Pharmacokinetics of intranasal corticosteroids. J Allergy Clin Immunol 2001;
108(1 Suppl):S26–31.
[59] Mackie AE, Ventresca GP, Fuller RW, et al. Pharmacokinetics of intravenous fluticasone
propionate in healthy subjects. Br J Clin Pharmacol 1996;41(6):539 – 42.
[60] Suarez S, Gonzalez-Rothi RJ, Schreier H, et al. Effect of dose and release rate on pulmonary
targeting of liposomal triamcinolone acetonide phosphate. Pharm Res 1998;15(3):461 – 5.
[61] Gonzalez-Rothi RJ, Suarez S, Hochhaus G, et al. Pulmonary targeting of liposomal
triamcinolone acetonide phosphate. Pharm Res 1996;13(11):1699 – 703.
[62] Waldrep JC, Gilbert BE, Knight CM, et al. Pulmonary delivery of beclomethasone liposome
aerosol in volunteers. Tolerance and safety. Chest 1997;111(2):316 – 23.
[63] Konduri KS, Nandedkar S, Duzgunes N, et al. Efficacy of liposomal budesonide in experimental
asthma. J Allergy Clin Immunol 2003;111(2):321 – 7.
[64] Ben-Jebria A, Chen D, Eskew ML, et al. Large porous particles for sustained protection from
carbachol-induced bronchoconstriction in guinea pigs. Pharm Res 1999;16(4):555 – 61.
[65] Talton J, Fitz-Gerald J, Singh R, et al. Nano-thin coatings for improved lung targeting of
glucocorticoid dry powders: in vitro and in vivo characteristics. In: Dalby R, Byron P, Farr SJ,
editors. Respiratory drug delivery VII. Buffalo Grove (IL)7 Interpharm Press; 2000. p. 67 – 74.
[66] Tunek A, Sjodin K, Hallstrom G. Reversible formation of fatty acid esters of budesonide, an
antiasthma glucocorticoid, in human lung and liver microsomes. Drug Metab Dispos 1997;
25(11):1311 – 7.
488 hÜbner et al