Gut, 1980, 21, 215-218

Rectally administered prednisolone-evidencefor a predominantly local actionD A H LEE, M TAYLOR, V H T JAMES, AND GEOFFREY WALKER*

From the Departments of Gastroenterology and Chemical Pathology, St. Mary's Hospital, London

SUMMARY Plasma prednisolone levels have been compared in healthy volunteers and in patientssuffering from idiopathic proctocolitis after the administration of standard retention enematacontaining either prednisolone-21-phosphate or prednisolone metasulphobenzoate sodium. Thelevels were significantly lower after the latter, irrespective of the presence or degree of activity of thedisease. Prednisolone metasulphobenzoate appeared to be as effective as the 21-phosphate ester forthe treatment of proctocolitis in the few patients where the two drugs were compared. It seemspossible that the beneficial effect of the form of therapy is exerted predominantly locally, ratherthan by systemic action.

The effectiveness of rectally administered predniso-lone in the treatment of idiopathic proctocolitis hasbeen well established since the early 1960s,' althoughwhether its predominant action is local or systemicor a combination of the two has been disputed.2-5In a recent communication,6 we concluded that thepredominant effect was exerted locally but thatsufficient prednisolone was absorbed for there alsoto be some systemic action.Most of the previous studies of the efficacy of

rectally administered prednisolone and its site ofaction have been of preparations containing pred-nisolone-21-phosphate. A retention enema con-taining prednisolone metasulphobenzoate sodium(Predenema: Pharmax) has been available forclinical use for several years, but its efficacy has notbeen formally tested.

In this study, we have compared plasma predni-solone levels in normal subjects and patients suffer-ing from idiopathic proctocolitis after administra-tion of the two preparations of retention enema.Although not designed as a clinical trial, this studyhas enabled us to obtain a clinical impression of theefficacy of prednisolone metasulphobenzoate in thetreatment of proctocolitis.

Methods

SUBJECTSNine subjects each received a standard prednisolone-21-phosphate retention enema which contains the

*Reprint requests to Dr G Walker.

equivalent of 20 mg prednisolone alcohol. Fourwere suffering from an acute exacerbation of procto.colitis as judged by symptomatology, sigmoido.scopic appearances, and rectal biopsy7 and anotherthree were entering remission after a variable periodof treatment with this form of therapy. The re-maining two subjects were healthy volunteers.

Eleven subjects each received a retentionenema of prednisolone metasulphobenzoate, whicbcontains the equivalent of 20 mg prednisolonealcohol. Seven had been diagnosed as having procto-colitis, three of whom had suffered a recent relapse.The remaining four subjects were healthy volunteers.Five of the 11 subjects had also been studied afterreceiving a prednisolone-21-phosphate enema (seeabove).The test enema was administered at 8.30 a.m.

Five millilitre blood samples were taken at 20minute intervals for four hours and then hourlyfor another three, through an indwelling cannulainserted in a forearm vein. The samples were takeninto lithium heparin tubes, and at the end of the testperiod were centrifuged and the plasma stored at-20°C until assayed. All the subjects remainedsupine after administration of the enema, which wasretained by each of them for at least four hours. Thepatients who were receiving therapy with predniso-lone retention enemata at the time of the study wereinstructed to administer their last one no later than24 hours before the start of the test.Plasma prednisolone levels were measured by a

radioimmunosassay technique that has been outlinedelsewhere.6 8 The samples were assayed using anantiserum to prednisolone which cross-reacted

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600

0

E 300

6 0 120 180 240 300 360 420m inutes

Fig. 1 Mean plasma prednisolone concentration-time profiles after administration ofprednisolone-21-phosphateto healthy subjects ( )arul to patients with colitis ( )and prednisolone metasulphobenzoate tohealthy subjects ( C)and to patients with colitis(O 0

slightly in vitro with cortisol (10%) and prednisone(5%). The specificity of the method was checked byassaying several samples with and without separa-tion of the prednisolone by paper chromatography.No significant difference was found between the twosets of results, except at time zero, which was prob-ably due to cross-reaction with cortisol. The plasmacortisol concentration always diminished over thetest period.

Results

The mean plasma prednisolone concentration-timeprofiles after administration of both preparations tonormal subjects and patients suffering from procto-colitis are shown in Fig. 1. After prednisolone-21-phosphate, appreciable amounts of prednisolonewere detectable in the peripheral circulation, both inpatients suffering from colitis and the healthy sub-

800

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jects. Disease activity did not affect plasma levels,but the two healthy subjects did achieve higherconcentrations, although the numbers were toosmall for statistical analysis. After prednisolonemetasulphobenzoate, peak plasma prednisolonelevels (CMAx) were significantly lower (P<O0001),and there was no difference between the patientswith colitis and the healthy subjects (0.4<P<0.5).Individual profiles are shown in Fig. 2. Five of thesubjects received both types of enema (Fig. 3) andin all of them plasma prednisolone levels were lowerafter the metasulphobenzoate preparation.Two of the subjects, and two others not included

in this study, were treated for an exacerbation ofproctocolitis for up to four weeks with prednisolonemetasulphobenzoate enemata. Three of them hadreceived treatment in the past with prednisolone-21-phosphate enemata, and were therefore able to makea subjective comparison between the forms of

Fig. 2 Individual plasma prednisolone concentration-time profiles after administration ofprednisolonemetasulphobenzoate.

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Rectally administered prednisolone-possible evidence for a predominantly local action

1000

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LAa)-6

Ec

(U 1000.c0

In 5

a" 500

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120 240 360 120 240 320Time (minutes)

Fig 3 Individual plasma prednisolone concentration-time profiles after administration ofprednisolone-21-phosphate(* *) and prednisolone metasulphobenzoate (0 O) in five subjects who received both preparations.

therapy. All four subjects responded to therapy withprednisolone metasulphobenzoate as judged by theimprovement in symptoms and sigmoidoscopicappearances. The clinical impression was that theresponse was as good as that usually seen aftertreatment with prednisolone-21-phosphate. Thethree patients who had received both preparationsalso felt that there was no difference between themin terms of their efficacy.

Discussion

Previous attempts to define the site of action ofrectally administered prednisolone have involvedthe use of enemata containing either the 21-phos-phate ester4 5 9-11 or radio-labelled methyl pred-nisolone.2 310 The amount of prednisolone thatwas absorbed (and hence conclusions about itspredominant site of action) was assessed by measur-ing either the concentration of the free steroid or theamount of radioactivity in a 24-hour urine collection.The results were inconsistent and opinions dividedas to whether the predominant site of action waslocal, systemic, or a combination of the two. Morerecently, in 1976, Powell-Tuck et al.5 comparedplasma levels after the rectal administration ofprednisolone-21 -phosphate with those achieved after

a similar dose of the drug had been given by n>cuth.They concluded that the beneficial effect of thisform of therapy was due to a combination of localand systemic action and noted similar plasma pred-nisolone levels after both modes of administration.By contrast, our own study revealed significantlyless rise in plasma prednisolone after the rectalpreparation than after an oral dose.

In the present study, we have demonstrated thatsignificantly less prednisolone reached the peripheralcirculation after administration of a retention enemacontaining the steroid as its metasulphobenzoateester than when the equivalent dose of rectal pred-nisolone-21-phosphate was given. It is possiblethat prednisolone metasulphobenzoate reached thecirculation intact (the ester itself would not bemeasured by the assay) but this is unlikely as it hasbeen demonstrated that for absorption to occur,steroid esters are usually hydrolysed in the bowellumen or mucosal cells.12 After oral administration,prednisolone metasulphobenzoate is hydrolysed13and a possible reason why more prednisolone wasdetectable in the circulation after the 21-phosphateester than after the metasulphobenzoate is that themilieu of the rectum and distal colon is inappropriatefor the hydrolysis of the latter. This explanation ofthe possible different behaviour of the two pred-

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nisolone esters is at present, however, only ahypothesis and could be confirmed by further in-cubation experiments with faecal homogenatesand/or biopsy material. However, some degree ofhydrolysis probably occurred because, in most ofthe subjects, prednisolone was detectable after ad-ministration of the metasulphobenzoate ester.Similar observations have been made for severaldifferent esters of cortisol which were equallyeffective in the treatment of proctocolitis. Thuscortisol acetate was not absorbed,1415 whereas theplasma cortisol concentration rose after rectaladministration of the hemisuccinate.4 16 17An alternative explanation for the detection of

prednisolone in the circulation after metasulpho-benzonate is also theoretically possible. The enemamay contain up to 4% prednisolone alcohol (per-sonal communication) and some at least of thecirculating steroid may have come from this source.

Although this study was not designed to be aformal trial, the clinical impression gained was thatprednisolone metasulphobenzoate administered as aretention enema was equally effective in the treat-ment of proctocolitis as prednisolone-21-phosphate.The finding of lower plasma prednisolone levelsafter the former suggests therefore that the predo-minant site of action of this form of therapy is local.A formal clinical trial to compare the efficacy ofthese two preparations would now seem to be in-dicated. If it is confirmed that prednisolone metasul-phobenzoate is equally effective, this might be thetreatment of choice, because only small amounts ofprednisolone reach the systemic circulation, therebyreducing the risk of side-effects.

This work and DAHL were supported by theMedical Research Council, Grant No. G974/615/S.GMT was supported by Grant No. C/16/407/1 fromthe North West Thames Regional Health Authority.The authors gratefully acknowledged the assistanceand co-operation of Pharmax Ltd.

References

1Matts SGF. Intrarectal treatment of 100 cases ofulcerative colitis with prednisolone-21-phosphate ene-mata. Br Med J 1961;1: 165-8.

2Spencer JA, Kirsner JB, Palmer WL. Rectal absorptionof 6-alpha-C14-H3-prednisolone. Proc Exp Biol Med1959; 103: 74-7.3Sanbar SS, West KM. Rectal absorption of radioactive6-alpha methyl prednisolone in ulcerative colitis.J Med Liban 1961; 14: 380-6.4Wood WA, Walters G, Matts SGF. Urinary excretionof prednisolone after intrarectal therapy in ulcerativecolitis. Br Med J 1964; 2: 1045-6.5Powell-Tuck J, Lennard-Jones JE, May CS, Wilson CG,Paterson JW. Plasma prednisolone levels after adminis-tration of prednisolone-21-phosphate as a retentionenema in colitis. Br Med J 1976; 1: 193-5.6Lee DAH, Taylor GM, James VHT, Walker G. Plasmaprednisolone levels and adrenocortical responsivenessafter administration of prednisolone-21-phosphate as aretention enema. Gut 1979; 20: 349-55.7Baron JH, Connell AM, Lennard-Jones JE. Variationbetween observers in describing mucosal appearances inproctocolitis. Br Med J 1964; 1: 89-92.8Lee DAH, Taylor GM, Walker JG, James VHT. Theeffect of food and tablet formulation on plasma pred-nisolone levels following administration of enteric-coated tablets. Br J Clin Pharmacol 1979; 7: 523-28.9Matts SGF, Wharton BA, Kelleher J, Walters G.Adrenal cortical and pituitary function after intrarectalsteroid therapy. Br Med J 1963; 2: 24-6.°0Halvorsen S, Myren J, Aakvaag A. On the absorption ofprednisone and prednisolone disodium phosphate afterrectal administration. Scand J Gastroenterol 1969; 4:582-4.

"Multicentre Trial. Betamethasone-17-valerate and pred-nisolone-21-phosphate retention enemata in procto-colitis. Br Med J 1971; 3: 84-6.

12Schedl HP, Absorption of steroid hormones from thehuman small intestine. J Clin Endocrinol 1965; 25:1309-16.3English J, Chakraborty J, Marks V, Trigger DJ,Thomson AG. Prednisolone levels in the plasma andurine: a study of two preparations in man. Br J ClinPharmacol 1975; 2: 327-32.4Nabarro JDN, Moxham A, Walker G, Slater JDH.Rectal hydrocortisone. Br Med J 1957; 2: 272-4.5Patterson M. Studies on the absorption of hydro-cortisone from the colon of patients with idiopathiculcerative colitis. Tex Rep Biol Med 1958; 16: 508-14.

16Macdougall I. Treatment of ulcerative colitis withrectal steroids. Lancet 1963; 1: 826-7 (letter)."Sampson PA, Brooke BN. Absorption of hydro-cortisone from the large bowel. Lancet 1963; 1: 701-2(letter).