Pharmacokinetics and Rectal Bioavailability of Hydrocortisone Acetate HELMUTMOLLMA"*, JURGEN BARTH*,CARSTEN MOLLMA"*, SABINE TUNN*, MICHAELKRIEG*, AND HARTMUTDERENDORF'*' Received Au ust 30,1990, from the ' D e p a p e n f of Pharmaceufics, College of Pharmacy, Box J-494, University of Florida, Accepted for publication December 1 1 , 1990. Gainesville, %I 32610, and the *Medical Clinic, University of Bochum, West Germany. The phanacokinetics and bioavailability of hydrocortisone after rectal administration of a hydrocortisone acetate foam was determined. Endogenous hydrocortisone was suppressed by dexamethasone administration. Plasma levels were compared with those observed after iv and oral administration. Only a very small part of the rectal dose (100 mg) was absorbed;the mean absolute bioavailability was 2%. There was substantial intersubject variability. Maximum hydrocortisone levels were reached after 2 h and averaged 35 ng/mL. These levels were 10-fold lower than those obtained after oral administration of a fivefold lower dose (20 mg) of hydrocortisone in the same subjects. Abstract
Local corticosteroid therapy of ulcerative colitis and Crohn's disease has been shown to be effective.'.' Dosage forms that have been used for rectal steroid delivery include hydrocortisone retention enemas (Cortenema) and a foam containing hydrocortisone acetate (Colifoam). Retention enemas are not very convenient for the patient and the relatively large volumes (60mudose) are sometimes difficult to retain. The foam (1g) is delivered to the rectum with a special applicator and has been shown to reach the midsigmoid colon in patients with the active d i ~ e a s eThis . ~ preparation is easily retained and clinically effective.'*' This local treatment is based on the concept that a high activity of the steroid can be produced a t the site of administration and, at the same time, the degree of systemic side effects can be minimized. However, there is little information on the degree of systemic absorption of hydrocortisone acetate after rectal administration. The Physician's Desk Reference' states that up to 30% of hydrocortisone acetate is absorbed when given as a retention enema. In a recent s t ~ d yit, ~was shown that morning serum levels of hydrocortisone were unchanged 12 and 36 h after application of the hydrocortisone acetate foam. The authors concluded from their results that hydrocortisone acetate was not significantly absorbed. However, the design of the study did not allow differentiation between endogenous hydrocortisone and hydrocortisone that was absorbed from the foam. It was the purpose of this study to determine the degree of hydrocortisone absorption after rectal administration of hydrocortisone acetate. Plasma levels were compared with those observed after iv and oral administration. During the study, endogenous hydrocortisone was suppressed by oral administration of dexamethasone, thus allowing for a specific evaluation of the exogenous hydrocortisone.
Experimental Section The pharmacokinetics of hydrocortisone after rectal administration of 100 mg of hydrocortisone acetate (Colifoam, TrommsdorE, West Germany) was investigated and compared with data obtained after iv and oral administration of a 20-mg dose (Hydrocortisone Hoechst) to eight healthy male subjects in a three-way crossover design. The average age of the subjects was 28 years, the average OO22-3~9/91/O9OO-0835$01 .OO/O 0 1991, American Pharmaceutical Association
weight was 74 kg. Endogenous hydrocortisone production was suppressed to < 10 ng/mL by oral administration of 4 mg of dexamethasone at 10 p.m. the day before the study. The mean hydrocortisone pre-dose level was 8.3 It 1.3 ng/mL. Blood samples were taken immediately before drug administration and aRer 10,20,30,40,60, 90, 120, and 150 min, and after 3, 4, 5, 6, 8, 10, 12, 14, and 24 h. Hydrocortisone concentrations were measured by radioimmunoassay (Coat-A-Count, Diagnostics Product Corporation, Bad Nauheim, FRG) in serum and corrected for the individual pre-dose levels. The data were subjected to noncompartmental pharmacokinetic analysis. Noncompartmental Pharmacokinetic A n a l y s i e T h e area under the plasma concentration-time curve (AUC) was calculated using the trapezoidal rule. Mean residence time (MRT) was calculated as area under the first moment curve (AUMC) divided by AUC. The AUMC was determined using a plot of the product of plasma concentration and time (Cp t ) versus time and calculation of its AUC value by the trapezoidal rule. The volume of distribution at steady state (Vd,) was determined as the product of total body clearance and mean residence time (CL * MRT). The bioavailability (BA) of hydrocortisone a h r rectal administration was calculated as AUC,,,, Di,/(AUCi, * Dr&) 100.The mean absorption time (MAT) of hydrocortisone after - MRT,,. The rectal administration was calculated as MRT,,, maximum plasma concentration ) ,C( is the experimental value with the highest plasma concentration. The time of the maximum plasma concentration (t,& is the experimental data point when , C was measured.
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Results Pharmacokinetics of Hydrocortisone after Intravenous and Oral Administration-Results for the pharmacokinetics of hydrocortisone after iv and oral administration have been described elsewhere in detail.6 After iv administration, hydrocortisone shows the classical biexponential plasma concentration profile (Figure I). The CL is 18.2 ? 4.2 L/h, the terminal half-life (tl,2) is 1.7 ? 0.5 h, the MRT is 1.9 t 0.4h, and Vd, is 34 5 5 L. These parameters were determined by noncompartmental analysis. After oral administration, hydrocortisone levels show a terminal t,,, of 1.8 t 0.5 h, which is identical to that after iv administration. The absolute BA averages 96 t 20%, indicating complete oral absorption. The MRT is 3.2 ? 0.5h, which is composed of the MAT (1.2t 0.5 h) and the MRT after iv administration (1.9 t 0.4 h). Maximum hydrocortisone levels of 305 ? 57 ng/mL were observed after 1.2 5 0.4 h. Pharmacokinetics of Hydrocortisone after Rectal Administration of Hydrocortisone Acetate-After rectal administration of hydrocortisone acetate, hydrocortisone levels are very low (Figure 1). The AUC was 109 t 45 ng * WmL, and the absolute BA averages 2.0 t 1.0%, indicating very low systemic absorption from the rectum. Figure 2 shows the individual BA after oral and rectal administration. The MRT is 3.9 1.4h, which is composed of the MAT (1.5* 1.2h) and the MRT after iv administration (1.9 t 0.4 h). Maximum hydrocortisone levels of 35 t 24 ng/mL were observed after 2.1 t 0.9h. Hence, these levels are 10-fold lower than those
*
Journal of Pharmaceutical Sciences I 835 Vol. 80, No. 9, September 7 9 9 1
cortisone acetate. Plasma levels are very low, resulting in a low risk of systemic side effects. "he results are in contrast to those reported after oral administration of hydrocortisone acetate? where rapid absorption and conversion to hydrocortisone were observed. This is consistent with results that have been reported for methylprednisolone acetate in the cat? where the BA after rectal and oral absorption was 13 and 93%,respectively. In the same study, it was reported that no methylprednisolone acetate could be detected after oral administration to a human subject, indicating rapid hydrolysis of the drug during absorption. "he results reported herein support the conclusion of a recent study' in which the suppression of the endogenous hydrocortisone was used as an indirect indicator for systemic absorption of exogenous steroid. Since no suppression had , , -I been observed, the authors concluded that the drug was not 0 2 4 6 8 10 12 absorbed. However, it also has been shown that suppression time [hours] of plasma hydrocortisone is a poor estimate of rectal absorption of glucocorticoids.gAfter administration of equal doses of Figure 1-Plasma concentration (mean 2 SD)of hydrocortisone after iv methylprednisolone acetate by the rectal and oral route,the (0)and oral (0)administration of 20 mg of hydrocortisone and rectal (0) plasma hydrocortisone levels were not significantly different administration of 100 mg of hydrocortisone acetate to eight subjects. from each other; but, plasma concentrations of methylprednisolone were significantly lower after rectal administration than after oral administration. Hence, the method applied in 2000 this study, using dexamethasone to suppress endogenous hydrocortisone, is a much more specific approach to inveatigate the problem. The extremely low bioavailability in combination with = E positive clinical reports about the therapeutic effectiveness'*' make hydrocortisone acetate foam a very safe and suitable '=. dosage form for local treatment of chronic inflammatory $ 1000 u bowel diseases. 1000
.
I
I
0
3
U
500
References and Notes
0
A
B
C
D
G
H
K
L
AVG
subject
Figure 2-Area under the curve (AUC) for each subject after iv, oral, and rectal administration. All areas are based on a dose of 20 mg of hydrocortisone.
obtained after oral administration of a fivefold lower dose.
Discussion The results of this study allow an assessment of absolute BA of hydrocortisone after rectal administration of hydro-
836 I Journal of PharmaceuticalSciences Vol. SO, No. 9,September 7997
1. Ruddell, W. S.J.; Dickinson, R. J.; Dixon, M. F.; Axon, A. T. R. Gut 1980,21,885-889. 2. Clark, M. L.Practitioner 1977,219,103-104. 3. Farthing, M.J. G.; Rutland, M. D.; Clark, M. L. Br. Med. J . 1979, 2 , 822-824. 4. Ph siciuns'Desk Reference, 40th ed.; Medical Economics: Oradell, NJ 1986,p 1446. 5. Neumann, G.;Niv, Y.; Bat, L.; Abramowich, D.; Shemesh, E. Zsr. J . Med. Sci. 1989,25,189-192. 6. Derendorf, H.;Mollmann, H.; Barth J . ; Mollman, C.; Tunn, S.; Krieg, M. J . Clin. P h a r m o l . , in press. 7 . Colburn, W. A.; DiSanto, A. R.; Stubbs, S. S.; Monovich, R. E.; DeSante, K. A. J . Clin. P h a r m o l . 1980,20,428436. 8. Garg, D. C.;Ng, P.;Weidler, D. J.;Sakrnar, E.;Wagner,J. G. Res. Commun. Chem. Pathol. P h a r m o l . 1978,22,3748. 9. Garg, D. C.; Weidler, D. J.; Sakmar, E.; Albert, K. S.; Wagner, J. G. Pharmacology 1980,21,38-42.
Local corticosteroid therapy of ulcerative colitis and Crohn's disease has been shown to be effective.'.' Dosage forms that have been used for rectal steroid delivery include hydrocortisone retention enemas (Cortenema) and a foam containing hydrocortisone acetate (Colifoam). Retention enemas are not very convenient for the patient and the relatively large volumes (60mudose) are sometimes difficult to retain. The foam (1g) is delivered to the rectum with a special applicator and has been shown to reach the midsigmoid colon in patients with the active d i ~ e a s eThis . ~ preparation is easily retained and clinically effective.'*' This local treatment is based on the concept that a high activity of the steroid can be produced a t the site of administration and, at the same time, the degree of systemic side effects can be minimized. However, there is little information on the degree of systemic absorption of hydrocortisone acetate after rectal administration. The Physician's Desk Reference' states that up to 30% of hydrocortisone acetate is absorbed when given as a retention enema. In a recent s t ~ d yit, ~was shown that morning serum levels of hydrocortisone were unchanged 12 and 36 h after application of the hydrocortisone acetate foam. The authors concluded from their results that hydrocortisone acetate was not significantly absorbed. However, the design of the study did not allow differentiation between endogenous hydrocortisone and hydrocortisone that was absorbed from the foam. It was the purpose of this study to determine the degree of hydrocortisone absorption after rectal administration of hydrocortisone acetate. Plasma levels were compared with those observed after iv and oral administration. During the study, endogenous hydrocortisone was suppressed by oral administration of dexamethasone, thus allowing for a specific evaluation of the exogenous hydrocortisone.
Experimental Section The pharmacokinetics of hydrocortisone after rectal administration of 100 mg of hydrocortisone acetate (Colifoam, TrommsdorE, West Germany) was investigated and compared with data obtained after iv and oral administration of a 20-mg dose (Hydrocortisone Hoechst) to eight healthy male subjects in a three-way crossover design. The average age of the subjects was 28 years, the average OO22-3~9/91/O9OO-0835$01 .OO/O 0 1991, American Pharmaceutical Association
weight was 74 kg. Endogenous hydrocortisone production was suppressed to < 10 ng/mL by oral administration of 4 mg of dexamethasone at 10 p.m. the day before the study. The mean hydrocortisone pre-dose level was 8.3 It 1.3 ng/mL. Blood samples were taken immediately before drug administration and aRer 10,20,30,40,60, 90, 120, and 150 min, and after 3, 4, 5, 6, 8, 10, 12, 14, and 24 h. Hydrocortisone concentrations were measured by radioimmunoassay (Coat-A-Count, Diagnostics Product Corporation, Bad Nauheim, FRG) in serum and corrected for the individual pre-dose levels. The data were subjected to noncompartmental pharmacokinetic analysis. Noncompartmental Pharmacokinetic A n a l y s i e T h e area under the plasma concentration-time curve (AUC) was calculated using the trapezoidal rule. Mean residence time (MRT) was calculated as area under the first moment curve (AUMC) divided by AUC. The AUMC was determined using a plot of the product of plasma concentration and time (Cp t ) versus time and calculation of its AUC value by the trapezoidal rule. The volume of distribution at steady state (Vd,) was determined as the product of total body clearance and mean residence time (CL * MRT). The bioavailability (BA) of hydrocortisone a h r rectal administration was calculated as AUC,,,, Di,/(AUCi, * Dr&) 100.The mean absorption time (MAT) of hydrocortisone after - MRT,,. The rectal administration was calculated as MRT,,, maximum plasma concentration ) ,C( is the experimental value with the highest plasma concentration. The time of the maximum plasma concentration (t,& is the experimental data point when , C was measured.
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Results Pharmacokinetics of Hydrocortisone after Intravenous and Oral Administration-Results for the pharmacokinetics of hydrocortisone after iv and oral administration have been described elsewhere in detail.6 After iv administration, hydrocortisone shows the classical biexponential plasma concentration profile (Figure I). The CL is 18.2 ? 4.2 L/h, the terminal half-life (tl,2) is 1.7 ? 0.5 h, the MRT is 1.9 t 0.4h, and Vd, is 34 5 5 L. These parameters were determined by noncompartmental analysis. After oral administration, hydrocortisone levels show a terminal t,,, of 1.8 t 0.5 h, which is identical to that after iv administration. The absolute BA averages 96 t 20%, indicating complete oral absorption. The MRT is 3.2 ? 0.5h, which is composed of the MAT (1.2t 0.5 h) and the MRT after iv administration (1.9 t 0.4 h). Maximum hydrocortisone levels of 305 ? 57 ng/mL were observed after 1.2 5 0.4 h. Pharmacokinetics of Hydrocortisone after Rectal Administration of Hydrocortisone Acetate-After rectal administration of hydrocortisone acetate, hydrocortisone levels are very low (Figure 1). The AUC was 109 t 45 ng * WmL, and the absolute BA averages 2.0 t 1.0%, indicating very low systemic absorption from the rectum. Figure 2 shows the individual BA after oral and rectal administration. The MRT is 3.9 1.4h, which is composed of the MAT (1.5* 1.2h) and the MRT after iv administration (1.9 t 0.4 h). Maximum hydrocortisone levels of 35 t 24 ng/mL were observed after 2.1 t 0.9h. Hence, these levels are 10-fold lower than those
*
Journal of Pharmaceutical Sciences I 835 Vol. 80, No. 9, September 7 9 9 1
cortisone acetate. Plasma levels are very low, resulting in a low risk of systemic side effects. "he results are in contrast to those reported after oral administration of hydrocortisone acetate? where rapid absorption and conversion to hydrocortisone were observed. This is consistent with results that have been reported for methylprednisolone acetate in the cat? where the BA after rectal and oral absorption was 13 and 93%,respectively. In the same study, it was reported that no methylprednisolone acetate could be detected after oral administration to a human subject, indicating rapid hydrolysis of the drug during absorption. "he results reported herein support the conclusion of a recent study' in which the suppression of the endogenous hydrocortisone was used as an indirect indicator for systemic absorption of exogenous steroid. Since no suppression had , , -I been observed, the authors concluded that the drug was not 0 2 4 6 8 10 12 absorbed. However, it also has been shown that suppression time [hours] of plasma hydrocortisone is a poor estimate of rectal absorption of glucocorticoids.gAfter administration of equal doses of Figure 1-Plasma concentration (mean 2 SD)of hydrocortisone after iv methylprednisolone acetate by the rectal and oral route,the (0)and oral (0)administration of 20 mg of hydrocortisone and rectal (0) plasma hydrocortisone levels were not significantly different administration of 100 mg of hydrocortisone acetate to eight subjects. from each other; but, plasma concentrations of methylprednisolone were significantly lower after rectal administration than after oral administration. Hence, the method applied in 2000 this study, using dexamethasone to suppress endogenous hydrocortisone, is a much more specific approach to inveatigate the problem. The extremely low bioavailability in combination with = E positive clinical reports about the therapeutic effectiveness'*' make hydrocortisone acetate foam a very safe and suitable '=. dosage form for local treatment of chronic inflammatory $ 1000 u bowel diseases. 1000
.
I
I
0
3
U
500
References and Notes
0
A
B
C
D
G
H
K
L
AVG
subject
Figure 2-Area under the curve (AUC) for each subject after iv, oral, and rectal administration. All areas are based on a dose of 20 mg of hydrocortisone.
obtained after oral administration of a fivefold lower dose.
Discussion The results of this study allow an assessment of absolute BA of hydrocortisone after rectal administration of hydro-
836 I Journal of PharmaceuticalSciences Vol. SO, No. 9,September 7997
1. Ruddell, W. S.J.; Dickinson, R. J.; Dixon, M. F.; Axon, A. T. R. Gut 1980,21,885-889. 2. Clark, M. L.Practitioner 1977,219,103-104. 3. Farthing, M.J. G.; Rutland, M. D.; Clark, M. L. Br. Med. J . 1979, 2 , 822-824. 4. Ph siciuns'Desk Reference, 40th ed.; Medical Economics: Oradell, NJ 1986,p 1446. 5. Neumann, G.;Niv, Y.; Bat, L.; Abramowich, D.; Shemesh, E. Zsr. J . Med. Sci. 1989,25,189-192. 6. Derendorf, H.;Mollmann, H.; Barth J . ; Mollman, C.; Tunn, S.; Krieg, M. J . Clin. P h a r m o l . , in press. 7 . Colburn, W. A.; DiSanto, A. R.; Stubbs, S. S.; Monovich, R. E.; DeSante, K. A. J . Clin. P h a r m o l . 1980,20,428436. 8. Garg, D. C.;Ng, P.;Weidler, D. J.;Sakrnar, E.;Wagner,J. G. Res. Commun. Chem. Pathol. P h a r m o l . 1978,22,3748. 9. Garg, D. C.; Weidler, D. J.; Sakmar, E.; Albert, K. S.; Wagner, J. G. Pharmacology 1980,21,38-42.
