Pharmacokinetics and pharmacodynamics of inhaled corticosteroids,☆☆,

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Abstract

There are significant differences in the pharmacokinetic properties of inhaled corticosteroids currently used in medical practice. All are rapidly cleared from the body but they show varying levels of oral bioavailability and more importantly variation in the rate of absorption after inhalation. Oral bioavailability is lowest for fluticasone propionate, indicating a low potential for unwanted systemic corticosteroid effects. Mathematical modeling has shown pulmonary residence times to be longest for fluticasone propionate and triamcinolone acetonide but shortest for budesonide and flunisolide. These properties appear to relate to pulmonary solubility, which appears to be the rate-limiting step in the absorption process. (J Allergy Clin Immunol 1998;101:S440-6.)

Section snippets

Prodrugs versus active drugs

Most inhaled corticosteroids, including FP and BUD, are used in their pharmacologically active form. However, BDP is very different because it is a prodrug that first needs to be activated by hydrolysis. The active form of BDP is the respective monoester, beclomethasone-17-monopropionate.

Relative receptor affinity

With respect to their receptor affinity relative to dexamethasone (RRA = 100), FP has the highest affinity (RRA = 1800) followed by 17-BMP (RRA = 1345), BUD (RRA = 935), TAA (RRA = 233), and FLU (RRA = 180).1 In practical terms, this means that a 10-fold higher unbound concentration of FLU at the receptor site is needed to produce the same degree of receptor occupancy as FP. This fact also makes clear why inhaled corticosteroids should never be compared on the basis of equal weight doses but

Plasma protein binding

Because only the free, unbound drug is able to interact with the corticosteroid receptor, it is important to convert measured plasma or serum concentrations to the respective unbound concentrations. All inhaled corticosteroids show moderate to high levels of protein binding. TAA has the lowest plasma protein binding (71%)2 followed by FLU (80%),3, 4 BUD (88%),5 and FP (90%).6 BDP has been reported to be 87% bound to plasma proteins,7 but no data are available for 17-BMP.

Oral bioavailability

Inhaled corticosteroids are intended to provide localized therapy with immediate drug activity at the site of delivery in the lungs. However, it is well known that the greater part of an inhaled dose is swallowed and therefore available for undesired oral absorption, resulting in unwanted systemic corticosteroid effects. Hence an ideal inhaled corticosteroid should have minimum oral bioavailability. This goal has been achieved in the case of FP, which has an oral bioavailability of <1%.8 The

Pulmonary bioavailability

In general, corticosteroids are absorbed well from the lungs. Indeed it can be assumed that all the drug available at the receptor site in the lungs will be absorbed systemically. Corticosteroids administered by inhalation can therefore be detected in the blood, although the blood corticosteroid concentration represents the sum of pulmonary and orally absorbed fractions. For this reason it is difficult to separately assess the pulmonary bioavailability of those inhaled corticosteroids that also

Systemic clearance

One of the most important properties of inhaled corticosteroids is their rapid clearance after absorption, which minimizes systemic side effects (giving rise to the term “soft steroids”). In theory, the faster the systemic clearance, the higher the therapeutic index.

All of the currently used inhaled corticosteroids show a rapid systemic clearance that is of similar magnitude: systemic clearance was reported to be 84 L/h for BUD,5 69 L/h for FP,14 58 L/h for FLU,9 and 37 L/h for TAA.10 These

Volume of distribution

The volume of distribution is a pharmacokinetic parameter that allows quantification of tissue distribution. The larger its value, the greater the amount of drug located inside the peripheral body compartments. However, a large volume of distribution does not necessarily indicate higher pharmacologic activity in the peripheral body compartments because most of the drug is present in its pharmacologically inactive, bound form. Indeed the active, unbound drug concentration at steady state is

Elimination half-life

The elimination half-life of any drug is a secondary pharmacokinetic parameter that is dependent on the rate of systemic clearance and the volume of distribution. The elimination half-life quantifies how rapidly the plasma concentration changes but does not indicate the magnitude of this concentration. As a result of its large volume of distribution, FP has the longest elimination half-life of 7 to 8 hours, as measured after intravenous administration.14 The elimination half-life of BUD is 2.8

Terminal half-life after inhalation

The terminal half-life after inhalation can differ from the true elimination half-life after intravenous administration if absorption is slow and if it is the overall rate-limiting step (“flip-flop pharmacokinetics”). Hence a slower terminal elimination half-life after inhalation than after intravenous administration indicates slow absorption. This may be the case for FP because terminal half-life values of >10 hours have been reported after inhalation of this drug. Since FP is absorbed only

Accumulation

Accumulation is the term used to describe the increase in plasma drug concentration that may occur during multiple-dose administration until steady state is reached. The accumulation time is a function of the terminal elimination half-life of the drug. As a general rule, it takes approximately five terminal half-lifes to reach steady state. In the case of FP, this is equivalent to about 2 days. Steady state is reached in about half a day in the case of BUD and TAA and within 8 hours for FLU

Cortisol suppression

Cortisol suppression is the most frequently used surrogate marker for corticosteroid systemic activity. However, because of the circadian rhythm of cortisol release, analysis of cortisol suppression is complex. With the use of deconvolution methods, it is possible to convert the cortisol concentrations ( Fig. 1) into the respective cortisol release rates that can be well described by a set of two straight line equations (Fig. 2). 18

. Cortisol release profile, modeled by a set of two straight line

Conclusions

A comparison of the pharmacokinetic and pharmacodynamic properties of inhaled corticosteroids currently used in medical practice clearly reveals significant differences between these compounds. Although all of these agents show rapid systemic clearance after absorption, there are differences in oral bioavailability and absorption rate after inhalation. The last parameter is probably the most relevant property because it reflects pulmonary residence time after inhalation and therefore duration

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    From athe University of Florida, Gainesville; and bthe University of Bochum, Bochum, Germany.

    ☆☆

    Reprint requests: H. Derendorf, PhD, Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610.

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