new perspectives inhaled drug delivery systemic bioactivity · the drug concerned and its inhaler...

Thorax 1995;50:105-110

THORAX

Editorials

New perspectives on inhaled drug delivery and systemicbioactivity

The inhaled route of administration is widely accepted asbeing the optimal way of giving drugs such as cortico-steroids and 32 agonists for the treatment of patients withairflow obstruction. It is possible with the inhaled route todeliver relatively small doses of drug to produce high localconcentrations in the airway, and at the same time minimiseabsorption into the systemic circulation. There are somepatients with more severe airflow obstruction who maybenefit from higher than conventional doses of inhaledcorticosteroid and 2 agonist, and indeed this practiceappears to have gained widespread acceptance amongstmany respiratory physicians. Whilst higher doses of thesedrugs may produce an improved airway response, it is wellrecognised that there is also a dose-response relationshipin terms of systemic adverse effects, both for inhaledcorticosteroids and for 2 agonists.12 The factors whichdetermine systemic absorption from the gut and lung havebeen given little consideration. In this respect there arenow an increasing number of new inhaler delivery systemswhich are designed to optimise lung deposition, and it istherefore important to know how this might alter thesystemic bioavailability. The spectrum of systemic adverseeffects of inhaled corticosteroids and 02 agonists will notbe discussed further in this article as they have beenextensively reviewed elsewhere.l

Factors determining systemic bioactivityIn general terms systemic bioactivity will be determinedby pharmacokinetic and pharmacodynamic properties ofthe drug concerned and its inhaler delivery system. Sys-temic bioavailability of inhaled drugs may arise from ab-sorption from the gastrointestinal tract or the lung. Thesystemic bioavailability from gut and lung vascular bedswill, in turn, be determined by the respective first-passmetabolism prior to absorption. Furthermore, systemicabsorption across the mucosal barrier will also depend onthe relative lipid solubility ofthe drug being delivered. Oncethe drug has been absorbed into the systemic circulation itsrate of elimination will determine its clearance from thecirculation and hence its half life. The pharmacodynamicfactors determining systemic bioactivity are the affinity andpotency of the drug at its receptor site of action. Theensuing discussion will focus primarily on pharmacokineticfactors rather than pharmacodynamic factors.

Gastrointestinal bioavailabilityMost of the nominal dose leaving an inhaler device (ap-proximately 80%) is deposited in the oropharynx which isendowed with a rich vascular network but has a relatively

small surface area available for systemic absorption. Drugabsorption across the buccal mucosa occurs directly intothe systemic circulation and avoids first-pass hepatic orintestinal metabolism. Absorption from the buccal cavitywill depend on the degree of lipid solubility and ionisation(pKa) as well as the prevailing pH.5 The polarity andpoor lipid solubility of salbutamol when given sublinguallyexplain why there is negligible absorption from this route.6In support of this, Collier and coworkers7 showed that thesystemic P2-mediated effects of metered doses of sal-butamol aerosol occur only when it is inhaled into thelung, but not when it is sprayed directly into the buccalcavity. Likewise, other clinical studies have shown thatmouth rinsing and the use of a large volume spacer do notattenuate systemic 2 effects of inhaled salbutamol.89 Thus,systemic absorption of inhaled salbutamol occurs pre-dominantly from the vascular bed of the lung rather thanthe gut. The pharmacokinetic plasma profile for inhaledsalbutamol would also support lung vascular absorption asthe maximum plasma concentration is achieved within fiveminutes, which is similar to that following an intravenousinjection. The fraction of salbutamol which reaches theintestine after swallowing undergoes extensive first-passsulphate conjugation, probably in the intestinal mucosaitself. 1

For inhaled corticosteroids the situation is somewhatdifferent. Firstly, the high degree of lipid solubility wouldbe expected, on first principles, to be associated withsignificant buccal absorption. The degree of buccal ab-sorption is, however, probably limited by the small availableabsorptive surface area as well as the relatively short mu-cosal exposure time before swallowing occurs. Whilst buc-cal absorption of inhaled corticosteroids avoids first-passmetabolism, absorption from the intestine undergoes anextensive degree offirst-pass hepatic metabolism. The first-pass metabolism for oral beclomethasone dipropionate isapproximately 80%, for budesonide 89%, and for flu-ticasone propionate 99%."- 3 Whilst beclomethasone di-propionate is biotransformed to its active metabolite (17-beclomethasone monopropionate) in the lung, there is noknown first-pass biotransformation of either budesonideor fluticasone propionate. This, in turn, will clearly in-fluence the total systemic bioavailability of budesonide andfluticasone in terms of the relative components of lung andgut absorption.The effect of mouth rinsing on the oral bioavailability

of budesonide has been studied in some detail. Selroosand coworkers'4 showed that the use of mouth rinsing withwater after inhalation of budesonide Turbohaler 1-6 mgresulted in a 15% mean reduction in systemic bioavailabilityas assessed by suppression of early morning cortisol levels.

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99% First-pass No first-pass

Systemiccirculation

A B C

Figure 1 Schematic representation of systemic bioavailability of threehypothetical inhaled corticosteroids (A, B, and C) in a dose of 1000 ig

given by the same inhaler device, each with different degrees of hepaticfirst-pass metabolism, but with no first-pass in the lung. The figures fortotal systemic bioavailability (lung plus gut) and percentage lungbioavailability (lungltotal) are: A 250 ,ig (80%); B 225 /sg (89%); C205 ig (98%).

A

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I Systemic circulation ITotal bioavailability

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Gut 56% Lung 27%

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89% first-pass No first-pass

62 igg Systemic circulation 270 9ggTotal bioavailability1~~332 gg

1339lt

Figure 2 Schematic representation of systemic bioavailability of (A)fluticasone propionate and (B) budesonide given by respective dry powderinhaler devices. Approximate data for lung and gut deposition ofDiskhaler and Turbohaler in normal subjects are taken from refs 16 and28, and for hepatic first-pass from refs 12 and 13.

This figure is similar to that reported by Pedersen et al'5in a pharmacokinetic study measuring plasma budesonidelevels, where mouth rinsing and swallowing of a charcoalsuspension (so called charcoal block) resulted in an

approximately 20% reduction of the total systemic bio-

availability of budesonide Turbohaler 1 mg. The inferencefrom these two studies is that mouth rinsing should beroutinely employed when using dry powder inhaler devicessuch as the Turbohaler or Diskhaler, not only to reduceoral bioavailability, but also to reduce the propensity forproducing local adverse effects such as oropharyngeal can-didiasis. The effects of large volume spacer devices onsystemic bioavailability will be discussed below becausethis will be dependent on the relative effects of the spaceron oral and lung bioavailability.

Lung bioavailabilityOn the basis of the data from mouth rinsing and charcoalblock studies'45 it can be inferred that the systemic bio-availability of inhaled corticosteroids is mainly determinedby absorption across the lung vascular bed. In other words,although the greater part of an inhaled steroid dose isabsorbed from the gut, it is mostly inactivated by first-passmetabolism. It would also follow, therefore, that an inhalerdelivery system which improves lung deposition would, atthe same time, be expected to increase lung bioavailabilityand hence overall systemic absorption.

Let us consider as a working example the relative gutversus lung components of systemic bioavailability for threedifferent inhaled corticosteroids given in a dose of 1000 jigvia the same delivery system (fig 1). For the purposes ofthis example the percentages for lung and gut depositionhave been rounded up to 20% and 50% respectively, withthe data being taken from the study of Melchor et all6 fora metered dose inhaler using the technetium labellingmethod for salbutamol. It is clearly evident from thesecalculations that, even when hepatic first-pass metabolismis increased beyond 90%, there is relatively little impacton the total systemic bioavailability of each of the threeinhaled corticosteroids. This once again indicates that it islung bioavailability which is the most important de-terminant of total systemic bioavailability for drugs suchas budesonide and fluticasone propionate which have ex-tensive first-pass hepatic metabolism. As a consequence ofthis, inhaler devices which improve lung deposition willincrease systemic bioavailability to a proportionately greaterdegree because of the absence of any first-pass effect inthe lung. It should, however, be pointed out that the abovecalculations are only approximate for two reasons. Firstly,any direct buccal absorption into the systemic circulationhas not been taken into account. Secondly, it has beenassumed that lung bioavailability will be 100% of thenominal dose delivered to the lungs. Indeed, it is unclearas to the relative proportions entering the systemic cir-culation via the alveolar capillary bed compared with thebronchial circulation. In addition, no allowance has beenmade for the proportion of swallowed drug which is un-absorbed from the gut.On the basis of these calculations it is interesting to

compare the relative systemic bioavailability of inhaledfluticasone propionate and budesonide given via dry pow-der inhaler devices, namely the Diskhaler and Turbohaler(fig 2A, B). Ifthese inhaler devices were used in conjunctionwith mouth rinsing, thus effectively obviating oral bio-availability, one might predict that the systemic lung bio-availability would be at least twice as high with budesonideas with fluticasone for a given nominal dose of 1000 gg -that is, 270 jg versus 120 jig. In this respect, two recentstudies have evaluated the single dose and steady statesystemic bioavailability of budesonide Turbohaler and flu-ticasone Diskhaler in normal volunteers. In a single doseranging study reported by Grahnen et al'7 the effects ofsingle inhaled doses of fluticasone propionate and bu-desonide were evaluated in terms of suppression of the

Gut 50% Lung 20%

Deposition

A9 +90% 95%

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area under the plasma cortisol levels versus time curvefor 0-20 hours (AUCo 20) after drug administration. Thepercentage suppression from placebo was 8% for flu-ticasone 250 1tg, 19% for fluticasone 500 jig, and 28% forfluticasone 1000 tg, in comparison with 16% for bu-desonide 800,ug. A further evaluation after seven doses offluticasone propionate 1000 jig twice daily resulted in 65%suppression of cortisol AUCo 2O1 These results are clearlyconsistent with the hypothesis that absorption offluticasoneacross the lung vascular bed occurs in a dose-relatedfashion, since the hepatic first-pass metabolism is close to100%. Furthermore, since mouth rinsing was employedin the study, buccal absorption was not responsible forproducing the systemic bioavailability which occurred.There also appears to be a difference in the degree ofadrenal suppression between single and repeated dosing,although this may simply be a reflection of the greater totaldaily dose given during the chronic dosing period (2000 ,ugdaily) compared with single dosing (1000,g daily).

In a study by Grove and coworkers'8 a randomisedcrossover design was used to compare budesonide 800 jgdaily given for one week followed by a further week of1600 gg daily, or fluticasone propionate 750 jig daily forone week followed by 1500 jg daily for one week. Therewas a one week washout between treatments with eitherfluticasone Diskhaler or budesonide Turbohaler whichwere both administered with mouth rinsing. Both flu-ticasone and budesonide produced comparable sup-pression of the tetracosactrin cortisol. response, withsignificant attenuation occurring at the lower dose. Therewas, however, no significant suppression of early morningcortisol or plasma osteocalcin levels with either drug. Thefindings of significant adrenal suppression with low dosesof fluticasone and budesonide despite the use of mouthrinsing would therefore infer that absorption across thelung vascular bed was the major determinant of systemicbioactivity for both of these inhaled corticosteroid drugs.Indeed, this would be in keeping with data from Bain et all9who, using a radioimmunoassay, demonstrated significantcirculatory levels of fluticasone following inhalation of1000 jg by metered dose inhaler in normal subjects, witha pharmacokinetic profile in keeping with rapid absorptionfrom the lung rather than from the gut.On the assumption that the lung bioavailability of flu-

ticasone propionate Diskhaler is 120 gig and that of bu-desonide Turbohaler is 270 jig (fig 2), the data on adrenalsuppression from the above two studies'7'8 would suggestthat fluticasone propionate exhibits greater systemic glu-cocorticoid activity than budesonide when appropriate cor-

rections are made for differences in lung depositionbetween the two devices. This is in contrast to theirequivalent topical glucocorticoid potency as assessed bythe vasoconstrictor assay, in that two separate studieshave shown both drugs to have twice the potency ofbeclomethasone dipropionate,20 21 with a further studyshowing the same potency in a direct comparison betweenthe two drugs.22 It would therefore be meaningful to com-pare the systemic bioactivity of fluticasone propionate andbudesonide given via the same inhalation device - forexample, a metered dose inhaler - as this would obviatedifferences in lung bioavailability between the two drypowder devices.

Larger multicentre studies in patients with moderateto severe asthma comparing high doses of fluticasonepropionate and beclomethasone dipropionate given bymetered dose inhaler have revealed conflicting results re-garding their relative systemic bioactivity. Fabbri et al+'found no significant differences in morning plasma cortisollevels, tetracosactrin response, or urinary free cortisol levelswhen comparing fluticasone propionate 1-5 mg/day with

beclomethasone dipropionate 15 mg/day. Bakke et aP'reported a significant fall in plasma cortisol (from 360 to226 nmol/l) and ACTH levels (from 34 to 22 ng/l) withfluticasone propionate 2 mg/day, whereas adrenal sup-pression was not detected with beclomethasone di-propionate 1 6 mg/day. Finally, Barnes and coworkers25demonstrated a 1*3-fold greater dose ratio for plasmacortisol suppression with beclomethasone dipropionatedespite a twofold difference in dose between fluticasonepropionate (1 mg/day) and beclomethasone dipropionate(2 mg/day).

Pharmacokinetic evaluation of lung depositionInitial attempts at evaluating inhaled drug deposition in-volved the use of technetium-99m labelled Teflon micro-spheres which were loaded into a pressurised aerosolcanister. After inhalation the proportion of radiolabelledparticles deposited in the lungs and oropharynx could thenbe quantified using a gamma camera detection system.26This technique has subsequently been refined using directlabelling of the drug with technetium. In one such studyin asthmatic patients the mean total lung deposition ofradiolabelled salbutamol was calculated at 18% for ametered dose inhaler and 11% for the Diskhaler dry powderdevice.'6 Similar figures have also been obtained for asth-matic subjects using radiolabelled salbutamol from anotherlaboratory with 19% deposition for a metered dose inhalerand 18% for the Autohaler breath activated device.27 Thereare, however, few available data on lung deposition ofinhaled corticosteroids. In a study reported by Borgstromet at28 using technetium-99m labelled terbutaline and bu-desonide delivered by a Turbohaler, the respective figuresfor total lung deposition for both drugs given by the samedevice in normal subjects were equivalent at 27% and 28%respectively. This suggests that the relative lipophilicity ofthese compounds does not materially affect lung de-position, at least as assessed with the radiolabelled tech-nique.More recently the pharmacokinetic approach has also

been applied to evaluate lung deposition on the assumptionthat peripheral lung deposition is associated with ab-sorption into the systemic circulation across the alveolarvascular bed. The direct pharmacokinetic technique isdependent, by definition, on the availability of a sufficientlysensitive bioassay for measuring low plasma concentrationsof a drug which are found with the inhaled route ofadministration. Another more indirect pharmacokineticmethod using salbutamol involves the measurement ofearly 30 minute urinary excretion of the native drug andits sulphate metabolite in order to differentiate betweenlung and gut bioavailability.29 The hypothesis that rapidabsorption across the lung vascular bed occurs is in keepingwith the pharmacokinetic time profile ofinhaled P2 agonistssuch as salbutamol and fenoterol, in that there is a rapidabsorption phase with peak plasma concentrations beingachieved within five minutes." By calculating phar-macokinetic parameters, such as maximum plasma con-centration and area under the concentration-time curve,it is possible to make comparisons between different inhalerdevices used for delivering the same drug.For example, in a study comparing a standard metered

dose inhaler and modified low velocity actuator device itwas found that the systemic absorption of inhaled sal-butamol was significantly greater with the modified ac-tuator device in terms of both peak levels and area undercurve (fig 3).3' The increased salbutamol absorption whichoccurred with the modified actuator was, in turn, associatedwith a left shift in the dose-response curve of systemic P2-mediated effects (fig 4). The difference in lung bio-

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o710-0 30 o5.0

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0 10 20 30Time (mins)

Figure 3 Plasma salbutamol concentration-timeminutes after inhalation of the final cumulative G(2600 /ig) given by standard metered dose inhalemodified low velocity actuawr device (0). Asterdifference between the two curves. Taken from reffrom Blackwell Scientific Publications, Oxford, L

0.1 r

*

IlI100 200 400 80C

Dose (ig)

*

*

200 400 80CDose (,ug)

100 200 400 80Dose (jig)

Figure 4 Dose-response curves with salbutamol.showing a left shift for the modified actuator dev,with the metered dose inhaler (0). Asterisks dendifference between the two devices at a given doswith permission from Blackwell Scientific Publicc

availability between the two devices was somewhat sur-prising in that previous radiolabelled deposition datacomparing the two devices had shown no differences interms of either total or peripheral lung deposition, whilstthe modified actuator reduced oropharyngeal deposition.32Thus, if systemic absorption of salbutamol had occurreddirectly from the buccal cavity or from the gut after swal-lowing, one might have expected the modified actuator tohave attenuated systemic salbutamol absorption which wasclearly not the case. Furthermore, it is difficult to accountfor the enhanced absorption of salbutamol across the lungvascular bed on the basis of the radiolabelled deposition

l data showing comparable peripheral lung deposition. The40 50 60 inference is that it may not be possible to extrapolate

directly from radiolabelled deposition data to compare twoformulations ofthe same drug (for example, generic drugs)

profile before and 60 or two delivery systems. It should also be pointed out,lose of salbutamol however, that in a study comparing the radiolabelled de-!r(0) and by aisks denote a significant position and urinary pharmacokinetic techniques using31 with permission terbutaline via a Turbohaler,33 overall lung deposition wasJK lower with the pharmacokinetic method (21% versus 27%).

There is further evidence to support the validity of thepharmacokinetic method from a study in which twonebulisers - the Hudson Updraft II and the Ventstreamnebuliser system - were compared.34 Since the Ventstreamproduces a considerable increase in output of respirableparticles as well as matching the nebuliser output to tidalflow rate, one might predict a difference in lung depositionbetween the two nebuliser systems. Using plasma sal-butamol levels for the pharmacokinetic evaluation, de-position with the Ventstream system was enhanced with

*\\ an approximate twofold improvement in lung delivery asassessed by comparison of the peak plasma concentrationor area under the concentration-time profile.The urinary pharmacokinetic method for evaluating lung

3 1600 3200 bioavailability can be refined by using the "charcoal block"technique in which oral activated charcoal suspension isused for mouth rinsing and swallowing to obviate oraland gut bioavailability. This enables calculation of lungdeposition if a standard radiolabelled intravenous injectionof the same drug is used as a pharmacokinetic internalstandard for comparison. In one such study the lung

* / bioavailability of inhaled budesonide was calculated at amean value of 32%, with the corresponding figures for ametered dose inhaler being 18%.35 Corresponding valuesfor total systemic bioavailability (lung plus gut) in the samestudy were 37% for the Turbohaler and 24% for themetered dose inhaler, giving a clear indication of relative

I lung versus gut bioavailability. Derom and coworkers,36D 1600 3200 also using the charcoal block technique with inhaled ter-

butaline in a dose of 500,g, found an approximately 2:1ratio between the two devices, although values for lungbioavailability were lower at 22% and 9% for Turbohaler

* _ and metered dose inhaler respectively. Clearly, if thesepharmacokinetic data are truly representative of lung de-livery, then the corollary should be that there is also a 2:1ratio in terms of efficacy. In this respect the bronchodilatorresponse to salbutamol shows a relative dose equivalenceof 50 gg versus 100 gg and 200 pg versus 400 pg for Tur-bohaler and metered dose inhaler respectively.37 In anotherstudy in subjects with acute asthma the bronchodilatorresponse to terbutaline 5 0 mg was found to be twice asgreat with Turbohaler as with a Nebuhaler spacer device."

o0 1600 3200 Unfortunately there are no direct comparisons betweenTurbohaler and metered dose inhaler using the technetiumradiolabelling method, although lung deposition

for systemic 12 effects data from different studies with these two devices 1628,ice (0) in comparison would certainly not predict the 2:1 ratio obtained with theoTaksignificantf 31 pharmacokinetic method. Furthermore, in the study byitions, Oxford, UK Melchor et al,6 although total and peripheral lung de-

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position with the large volume spacer was significantlybetter than with the Diskhaler, this was not associated withany difference in bronchodilator response to 200 ,ug inhaledsalbutamol, once again possibly questioning the validity ofthe radiolabelled deposition technique.

Other factors affecting lung deposition andbioavailabilityFrom first principles one might expect that lung deposition,and hence lung bioavailability, might be altered in patientswith airflow obstruction as a consequence of narrowedperipheral airway calibre and reduced access to the alveolarvascular bed. This indeed appeared to be the case in thestudy of Melchor et al'6 where peripheral lung depositionwas significantly higher in normal subjects than in asthmaticpatients, and this difference was uniformly observed withthe metered dose inhaler, large volume spacer, and Disk-haler delivery systems. Despite an approximately twofoldgreater baseline FEV, in normal compared with asthmaticsubjects, the difference in lung deposition between the twogroups was approximately 1*5-fold. Unfortunately thereis no similar comparison between normal and asthmaticsubjects in terms of lung bioavailability using the phar-macokinetic technique. There is, however, some indirectevidence - albeit from two different studies - comparingthe pharmacokinetic profile of 4 mg inhaled fenoterol innormal and asthmatic subjects using identical metereddose inhaler devices.'039 The FEV5, expressed as percentagepredicted, was 56% in the asthmatic subjects and wasassociated with an approximate two-fold difference in peakplasma fenoterol concentration (1 *6 ng/ml in asthmaticsand 3 1 ng/ml in the normal subjects). Indeed, the differ-ence in plasma fenoterol levels between the two groupswas associated with a marked difference in the maximalheart rate response to fenoterol 4 mg, being greater in thenormal subject group. It is also evident that enhancedsystemic absorption across the lung vascular bed is as-sociated with increased P,-mediated systemic effects, aswas shown by Newnham et al in a study comparing themetered dose inhaler and modified actuator device (fig4).31For delivery of high doses of inhaled corticosteroid the

routine use of a large volume spacer has been advocated,not only to reduce local side effects such as candidiasisbut also to reduce systemic absorption from the oropharynxand gut. The net result of adding a large volume spacerwill depend upon the relative effects of the spacer on lungand gut bioavailability. For example, Melchor et al,16 usingradiolabelled salbutamol in asthmatic patients, showed thatthere was a mean reduction in gut deposition from 50%to 6% along with a concomitant increase in peripheral lungdeposition (as a percentage total) from 30% to 39%.Toogood et al'0 calculated potency ratios for inhaled bu-desonide given via a pear-shaped spacer in comparisonwith a metered dose inhaler and showed a reduction inoropharyngeal candidiasis, increased delivery to the lungas assessed by peak flow measurements and spirometry, aswell as an increase in systemic bioactivity as assessed byeffects on early morning serum cortisol levels and bloodeosinophil count. The increased systemic bioactivity usingthe pear-shaped spacer attachment is perhaps not entirelysurprising since net gains from enhanced lung depositionwould be expected to outweigh net losses from attenuatedoral deposition. This study therefore further supports thehypothesis that lung bioavailability is the major determinantof systemic bioactivity.

In a study reported by Brown and coworkers4' in asth-matic patients taking high doses of either inhaled bu-desonide or beclomethasone dipropionate (>1 mg/day) a

comparison was made of adrenal suppression using ametered dose inhaler with or without a large volume spacer.The results showed no difference between the metereddose inhaler and spacer groups in terms of the proportionof cases with adrenal suppression, or in terms of the doseof inhaled corticosteroid causing suppression. Data fromthe same laboratory in normal volunteers comparingmetered dose inhaler and large volume spacer for deliveryof 2 mg/day of either budesonide or beclomethasone di-propionate showed conflicting results.42 Beclomethasonedipropionate given by metered dose inhaler produced sig-nificant suppression of 24 hour urinary free cortisol ex-cretion compared with placebo, and this effect was almostcompletely abolished by the large volume spacer used inconjunction with beclomethasone. It was not possible tomake any inference on the effects of the large volumespacer on budesonide bioavailability because the metereddose inhaler on its own did not significantly suppressurinary free cortisol compared with placebo. This effect ofthe large volume spacer with beclomethasone dipropionatewas also shown in asthmatic subjects in terms ofproducingreduced adrenal suppression with the spacer device.43 Onepossible explanation to account for the apparent dis-crepancy between beclomethasone dipropionate and bu-desonide might be that the reduction in oral and gutbioavailability with the spacer would be relatively moreimportant for beclomethasone in view of its lesser degreeof hepatic first-pass metabolism. In other words, withbeclomethasone dipropionate using the large volumespacer, the net loss from gut bioavailability would outweighthe net gain from lung bioavailability with a resultantoverall reduction in total systemic absorption.

Conclusions and the way forwardThere is accumulating evidence from pharmacokineticstudies to suggest that absorption across the lung vascularbed is an important determinant of systemic bioactivityand adverse effects, this being particularly the case withinhaled corticosteriods where there is extensive first-passmetabolism in the liver but not in the lung. As a result thedevelopment ofnew inhaler delivery systems with improvedlung deposition may increase systemic bioactivity at thesame time as increasing topical airway activity. The use ofpharmacokinetic evaluation may also reliably predict lungdeposition for drugs such as inhaled P2 agonists and corti-costeroids where it is possible to quantify lung bio-availability. In this respect, studies are needed to comparedirectly the pharmacokinetic and radiolabelling methodsfor evaluating lung deposition and to compare these tech-niques in both normal and narrowed airways. The phar-macokinetic technique may also be applicable to theevaluation of the bioequivalence of generic inhaled drugformulations. For the future it is also possible that theinhaled route of administration might be used for systemicadministration of certain drugs via the lung vascular bed,particularly where a rapid onset of action without first-pass metabolism is required as, for example, with a nicotineinhaler delivery system.

Department of Clinical Pharmacology,Ninewells Hospital and Medical School,University of Dundee,Dundee DDI 95Y,UK

B J LIPWORTH

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