The pharmacokinetics and transdermal delivery of loteprednol etabonate and related soft steroids

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drug delivery reviews Advanced Drug Delivery Reviews 14 (1994) 293-299

ELSEVIER

The pharmacokinetics and transdermal delivery of loteprednol etabonate and related soft steroids a

Thorsteinn Loftsson

~'

' ,

Nicholas Bodor b

aDepartment o f Pharmacy, University of Iceland, P.O. Box 7210, 1S-127 Reykjavik, Iceland," bCenter for Drug Discovery, University of" Florida, Gainesville, FL 32610-0497, USA

(Received April 16, 1992; Accepted August t7, 1992)

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

293

1. Introduction ....................................................................................................................................

294

2. The degradation of soft steroids in vitro ..............................................................................................

294 /

3. The pharmacokinetics of soft steroids ..................................................................................................

295

4. Transdermal delivery of soft steroids ...................................................................................................

297

5. Conclusions .....................................................................................................................................

298

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

298

Abstract The soft steroids are relatively stable compounds in aqueous buffer solutions and in plasma in vitro, but they are effectively hydrolyzed to the designed metabolites in vivo. Thus, loteprednol etabonate (1: 17~-ethoxycarbonyloxy-A Icortienic acid chloromethyl ester) is hydrolyzed to 17~-ethoxycarbonyloxy-ALcortienic acid (2) and then to AI-cortienic acid (3) in vivo. The pharmacokinetic profile of i has been evaluated in dogs and rats and the tissue levels of 1 determined in rats after intravenous administration. In dogs 1 was distributed according to a two-compartment model characterized by a terminal half-life of 2.8 h, a high volume of distribution (Vd~re~ - 3.7 I/kg), a clearance of 0.9 I/h/kg, and high protein binding (about 95%). No intact ! could be detected in plasma after oral administration of I to dogs. In rats 1 was distributed according to a three-compartment model characterized by a terminal half-life of 51 min. In a separate study the terminal half-life of 2 in rats was determined to be 20 min. The permeability of the soft steroids

*Corresponding author. 0169-409X/94/$27.00 ,~', 1994 Elsevier Science B.V. All rights reserved SSDI 0 1 6 9 - 4 0 9 X ( 9 3 ) E 0 0 5 9 - N

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T. Loftsson. N. Bodor/Advanced Drug Deliver), Reviews 14 (1994) 293-299

through skin or mucous membrane is similar to or better than the permeability of comparable hard steroids. In this short review we demonstrate how a successful design of a soft corticosteroid was obtained. Key words." Aqueous solutions; Degradation; Metabolism; Permeability; Review; Soft corticosteroids; Stability; Tissue distribution; Toxicity

1. Introduction The therapeutic index of a drug is generally defined as the ratio of the median lethal dose (LDs0) to the median effective dose (EDs0), but in clinical studies the therapeutic index is often evaluated by comparing the plasma concentration of a drug required to produce toxic effects to the concentration required for the therapeutic effects. The value of the therapeutic index indicates how selective the drug is in producing its desired effects, i.e. drugs possessing a small therapeutic index generally require greater care in dosing than drugs with a large therapeutic index. This, however, is a simplification of a much more complex relationship. For example, the pharmacokinetic and pharmacodynamic variations in the population may be significant and the dose or plasma concentration of a drug required to produce a therapeutic effect in most of the population will usually overlap the concentration required to produce toxic effects in some of the population. Also, drug toxicity is a combination of a number of processes and factors. This includes not only all the different pharmacological effects of the drug itself, but also the various effects of the drug metabolites, intermediates and products formed by interactions of reactive intermediates with various components within the body. The main objective of soft drug design is to increase the therapeutic index of a drug through simplification of its metabolism and pharmacokinetics [1]. There are at least five different approaches to soft drug design: Soft analog, activated soft compounds, natural soft drugs, soft drugs based on the active metabolite approach, and soft drugs based on the inactive metabolite approach [2 6]. For example, the soft glucocorticoid, loteprednol etabonate (17ct-ethoxycarbonyloxy-A~-cortienic acid chloromethyl ester, 1), was designed by the inactive metabolite approach which can be sum-

marized as follows [2]: Pharmacological inactive and non-toxic metabolites of prednisolone, A 1cortienic acid (3), were identified and used as lead compounds. Chemical modifications were performed on 3 to obtain structures which resembled known active glucocorticoids. This reactivation was obtained through introduction of a chloromethyl carboxylate function at the 1713-position. Further activation was obtained by introduction of an ethylcarbonate ester in the 17~-position. Both moieties are metabolically labile (Fig. 1). The anti-inflammatory activity of 1 is comparable to that of betamethasone, one of the most active anti-inflammatory steroids, but 1 has much lower systemic side-effects, e.g. thymolitic activity and adrenal suppression, than betamethasone and other conventional steroids [2,7 9]. Also, both 17~-ethoxycarbonyloxy-Al-cortienic acid (2; A ~cortienic acid etabonate) and 3 have been shown to be biologically inactive [10]. The following is a short review of in vitro degradationstudies, and pharmacokinetic and transdermal delivery studies of loteprednol etabonate and related soft steroids, which have recently been performed in various animals.

2. The degradation of soft steroids in vitro Most in vitro studies have shown that the soft steroids and their hydrolysis products, the 17-esters, are relatively stable compounds (Table 1). Esterification of the alcohol group at the 17-posi-

OH

0

-OCOOC2H s

'

D

OH

-OCOOC2Hs

. 0

OH

• 0

Fig. l. Metabolicpathway of loteprednol etabonate.

-OH

T. Lofisson. N. Bodor/Advaneed Drug Deliver), Reviews 14 (1994) 293-299

295

Table 1 The structure of soft steroids and related compounds, and their half-life in aqueous hydrochloric acid (HC1) solution (pH 1, 13 and 50.8 4- 0.2°C), aqueous 0.01 M phosphate buffer (PB) solution (pH 7.40, ionic strength 0.10 (NaC1) and 37.0 _+ 0.2"C), aqueous sodium hydroxide (NaOH) solution (pH 12.0, ionic strength 0.10 (NaC1) and 23.0 4- 0.2°C), 80% human plasma (HP) diluted with anticoagulant citrate phosphate dextrose solution U.S.P. (37.0 4- 0.2°C) and rat liver homogenate (RLH - 37.0 4- 0.2°C). [T. Loftsson and N. Bodor, unpublished results]

IR C=O 1

0~ R 2 Compound

Ri

R2

Half-life (h)

no.

4 5 6 7 8 9 10 It 12

OCH2C1 OCH2C1 OCH2C1 OCH2CI OH CHzOH OCH2SCH3 OH OH

OH OCO2CH2CH 3 OCOCH2CH3 OCO2CH3 OCO(CH2)3CH 3 OCO(CH2)3CH3 OH OCOzCH2CH3 OCOCH2CH3

HCI

PB

NaOH

HP

RLH

2.2 12 5.8 10 * * 0.49

7.t 33 27 50 * * 15

0.01 2.1 1.1 0.85 * 0.03 0.24

2.2 9.3 5.3 16 * 8.7 38

0.12 2.3 4.6 4.9 29 14 1.8

*

*

*

*

*

,

•

*

•

(85)

*No degradation observed.

tion (at R2 in Table 1) appears to stabilize the chloromethyl ester (R1 - OCH2CI in Table 1) both in aqueous buffer solutions and biological fluids. For example, 7 is about 40-times more stable than 4 in rat liver homogenate. The 17-esters are more stable than the chloromethyl ester, the main degradation products of the diesters are the 17-monoesters, and an alcohol group in the 20-position (Ri - OH) stabilizes the 17-ester, and esters 11 and 12 are more stable than esters 5, 6 and 7. Common esterases, e.g., carboxylicester hydrolase (EC Yl.I.1), lipase (EC 3.1.1.3), butyrylcholinesterase (EC 3.1.1.8) and cholesterol esterase (EC 3.1.1.13), do not hydrolyze 1 in vitro. These results support observations by several investigators [6,9,11-13] that 1 is mainly metabolized in the body to 2 which then is either excreted unchanged, or conjugated or metabolized further to 3 before excretion (Fig. 1).

3. T h e p h a r m a c o k i n e t i c s

of soft steroids

As previously indicated, a soft drug is characterized by one-step metabolism to the inactive metabolite which then is relatively fast and effectively eliminated from the body. Frequently, the designed metabolite is very hydrophilic and, as such, is usually eliminated relatively fast and without further metabolism by urinary excretion. The amount of a given inactive metabolite in the body at any time after administration of the parent soft drug is a function of both its formation rate and its elimination rate, and since the elimination rate is much higher than the formation rate, the amount of metabolite in the body is usually much lower than that of the parent soft drug. Hochaus et al. [13] have evaluated the pharmacokinetic profile of loteprednol etabonate (1) in both rats and dogs. In rats, the tissue levels of intact drug (1) and its metabolites were highest in the liver, while other investigated organs (lung, brain, heart and kidney) did not show any drug

296

T. Loftsson, N. Bodor/Advanced Drug Deliver)' Reviews 14 (1994) 293 299

Table 2 The concentration of 1 and 2 in blood and various tissues after intravenous administration of 20 mg/kg of 1 to rats Time (min)

Concentration of 1 2 SE (gg/ml or ~tg/g) Blood

Brain

Kidney

Liver

Lung

5 40 150

22.6 ± 3.6 2.6 ± 0.2 0.51 _+ 0.14

35.2 ± 3.4 8.2 ± 0.7 *

99.5 _+ 28.1 72.8 ± 9.7 0.43 ± 0.10

102.0 + 7.1 15.3 + 2.4 1.1 _+ 0.1

41.8 + 6.1 8.8 + 0.6 *

Time (min)

Concentration of 2 _+ SE (/~g/ml or/~g/g) Liver

Lung

5 40 150

Blood

Brain

Kidney

1.8 ± 0.4 1.9 _+ 0.2 0. t0 _+ 0.04

0.32 ± 0.03 1.3 _+ 0.2 *

5.1 ± 0.25 11.0 + 1.5 1.l _+ 1.0

9.1 _+ 2.2 10.0 ± 0.5 0.07 ± 0.04

2.3 _+ 0.3 2.9 _+ 0.6 *

*Not determined. Four animals were used for each time point. From Ref. [6].

a c c u m u l a t i o n . A f t e r a single i n t r a v e n o u s injection o f I (5 m g / k g ) to dogs the p l a s m a c o n c e n t r a t i o n o f ! followed a t w o - c o m p a r t m e n t open m o d e l characterized by a t e r m i n a l half-life o f 2.8 h, a high v o l u m e o f d i s t r i b u t i o n (Vd 3.7 l/kg), a clearance o f 0.9 l/h/kg, a n d high p r o t e i n b i n d i n g ( a b o u t 95%). N o intact d r u g was f o u n d in the urine after i n t r a v e n o u s injection o f 1 and no intact d r u g c o u l d be detected in p l a s m a after oral a d m i n i s t r a tion o f 1 (5 m g / k g ) to dogs. N o d e g r a d a t i o n was o b s e r v e d in vitro in d o g b l o o d or plasma. These results, t o g e t h e r with other o b s e r v a t i o n s in b o t h rats a n d dogs, suggested a large first-pass effect o f 1 after oral a d m i n i s t r a t i o n . B o d o r et al. [6] d e t e r m i n e d the tissue levels a n d the p h a r m a c o k i n e t i c s o f b o t h I a n d its m e t a b o l i t e 2 in rats. The levels o f 1 a n d 2 in b l o o d and four tissues after single i n t r a v e n o u s injection o f a large dose o f I (20 m g / k g ) are shown in T a b l e 2. The highest c o n c e n t r a t i o n s o f b o t h 1 and 2 were f o u n d in the liver a n d in the kidney; much lower c o n c e n t r a t i o n s were o b s e r v e d in b l o o d a n d o t h e r tissues. These results, t o g e t h e r with the previously o b s e r v e d large first-pass effect, strongly suggest that the liver is the m a i n site o f m e t a b o l i s m when 1 is given systemically. The elevated level o f I a n d 2 in the kidney also indicates the i n v o l v e m e n t o f this o r g a n in the e l i m i n a t i o n o f I a n d its m e t a b o lite. In c o n t r a s t to w h a t was o b s e r v e d in d o g b l o o d . . . .

--

a n d p l a s m a , 1 was m e t a b o l i z e d relatively fast in rat b l o o d and p l a s m a in vitro with the c o n c u r r e n t a p p e a r a n c e o f 2. The b l o o d c o n c e n t r a t i o n o f b o t h I and 2 was m o n i t o r e d after single i n t r a v e n o u s injection o f 1 (20 m g / k g ) in rats [6]. The intact soft d r u g 1 was d i s t r i b u t e d a c c o r d i n g to a t h r e e - c o m p a r t m e n t open m o d e l with a t e r m i n a l half-life o f 51 min; the terminal half-life o f 2 was d e t e r m i n e d to be 40 min (Fig. 2). In a s e p a r a t e study the p h a r m a c o k i netics o f the m e t a b o l i t e 2 in rats was investigated.

102

.

.

.

.

I 60

I BO

- " "~"~k. b g c o U

10-~

10 .2

I 0

I 20

I 40

I 100

I 120

I 140

I 160

Time, min

Fig. 2. Mean blood concentration time profiles of loteprednol etabonate (1, O) and its metabolite (2, m) following intravenous administration of 20 mg/kg of | to rats. From Bodor et a~. [61.

T. Lol?sson, N. Bodor/Advanced Drug DeliveO, Reviews 14 (1994) 293 299

After an intravenous injection of 2 (10 mg/ml) the metabolite had a terminal half-life of 20 min. A three-compartment open model consists of: a central compartment which represents the blood and highly perfused tissues such as liver; a tissue compartment which represents the more slowly perfused tissues; and a deep tissue compartment representing poorly perfused tissues such as fat. Since the plasma concentration of 2 at any time after administration of its parent soft drug 1 is a function of its formation rate and its elimination rate, the high plasma concentration of I right after the intravenous injection results in relatively fast formation of 2 in the liver and consequently a high plasma concentration of 2. After the distribution of 1 within the body and equilibrium has been reached, the plasma levels of 2 should decline in parallel with the plasma levels of 1. Thus, although the real elimination half-life of 2 is much shorter than that of 1, the apparent half-life of 2 becomes comparable to the one of 1 when 2 is continuously formed from 1 in the body. Although the hydrophilic metabolite 2 has a much smaller volume of distribution, its plasma levels are much smaller than those of I which also show how effectively this metabolite is eliminated from the body. Compared to the traditional gluco-

297

corticoids the soft steroid 1 causes fewer side-effects due to both the formation of inactive metabolites and their effective excretion from the body [11.

4. Transdermal delivery of soft steroids Although the skin is one of the most accessible organs of the body, intact healthy skin is a remarkably good barrier to mass transport of topically applied drugs. The barrier for most drugs resides principally in the outermost layer of the skin, the stratum corneum. It is known that corticosteroids are ineffective as anti-inflammatory agents in dermatology unless they pass this barrier into the viable epidermis. Topical delivery of drugs is a complex process influenced by both the physicochemical properties of the drug molecule and the chemical composition of the vehicle. The skin barrier behaves like a passive diffusion barrier and a form of Fick's law can be used to describe the steady-state flux (I) through the barrier [14,15]:

DKp Cd

I

~

1

PCd

Table 3 The structure and the permeability coefficient (P) ± standard error of betamethasone 17-valerate (17) and some soft steroids through hairless mouse skin in vitro

NI C=O

0~ R 4 Compound no.

Ri

R~

R3

R4

RT (rain)"

P ( + S E ) x 10~ (cm/h)

I 13 14 15 16 17

H H H H F F

OCH2CI OCH:C1 OCH2F OCH2F OCH,F CH2OH

OCO2CH2CH3 OCO2CH(CH3)2 OCO2CH2CH3 OCO,CH(CHO: OCOeCH(CH02 OH

H H H H CH3 CH3

5.0 5.0 5.0 4.5 5.0 3.8

0.52 0.42 6.90 7.00 13.2 6.60

+ 0.09 +_ 0.05 _+ 0.59 _+ 6.02 + 0.6 + 0.40 b

"The retention time (RT) in HPLC (Cis llBondapack column, the mobile phase consisted of acetonitrile, 0.05 N aqueous acetic acid solution and water (6:1:3) and the flow rate was 2.0 ml rain). bThe permeability coefficient was determined from the amount of intact betamethasone 17-valerate found in the receptor phase, About 16% was hydrolyzed within the skin and in the receptor phase to betamethasone. From Ref. [16].

298

T. Loftsson, N. Bodor/Advanced Drug Delivery Reviews 14 (1994) 293 299 0.4

A

g 0,3

n-

0.2

c_

"¢

0.1

I.-

0.0

'~'

. " 10

, 20

~

Time

, 30

, 40

50

(h)

Fig. 3. Permeation profile of loteprednol etabonate (1) through hairless mouse skin in vitro at 34.5 _+ 0.5 °C. The vehicle consisted of aqueous 40% (w/v) heptakis (2,6-di-O-methyl)-[3-cyclodextrin solution saturated with 1. The solubility of 1 in the vehicle was determined to be 22.5 mg/ml and the results shown are the average of 3 experiments. [] = 1; O = 2; A = 1 + 2. From Loftsson and Bodor [unpublished results].

Michniak-Mikolajcak and Bodor [16] have determined the permeability of betamethasone 17-valerate (17) and five soft corticosteroids through hairless mouse skin (Table 3). Their results show that the molecular structure of the drugs tested has significant effects on their permeability through the skin. Bodor et al. [6] have investigated the effect of various vehicle systems on the transdermal delivery of 1 and found that its permeability coefficient ranged from 1 x 10 4 to 1 x 10 -5 cm/h depending on the composition of the vehicle system used. Also, the partition coefficient of the drug between the vehicle and the skin barrier is affected by the lipophilicity of the drug. The soft steroid 1 is about 5-times more lipophilic and permeates through hamster's cheek pouches at a much faster rate than hydrocortisone 17-valerate [17]. An example of a permeation profile for 1 through hairless mouse skin is shown in Fig. 3.

5. Conclusions

where D is the diffusion coefficient of the drug in the barrier, Kp is the effective partition coefficient of the drug between the vehicle and the barrier, Cd is the concentration of the dissolved drug in the vehicle and h is the effective thickness of the barrier. The permeability coefficient (P) is defined as the product of D and Kp divided by h. If the drug molecule is roughly spherical and the molecules of the surrounding barrier (solvent) are of comparable or smaller size, the diffusion coefficient can be expressed by the Stokes-Einstein equation: D

kT 6r

2

where k is the Boltzmann constant, T is the absolute temperature, r is the radius of the drug molecule and q is the viscosity of the barrier (solvent). The constants k, T and r I will not be affected by the molecular manipulations in the soft drug design, and since the molecular weight (or the radius) of the different soft steroids is almost constant, insignificant variations in the diffusion coefficient will be observed. Thus, the permeability (P) of the soft steroids through skin is mainly influenced by their partition into the skin barrier (Kp).

The pharmacokinetic profile and metabolism of loteprednol etabonate (1) have been investigated in several animal species. This soft corticosteroid is mainly hydrolyzed in vivo to the designed inactive metabolite. The experimental results of several investigators show that the predictable metabolism and controllable pharmacokinetics, obtained through molecular manipulations in the activation stage of the soft drug design, ensure the soft characteristics of the drug molecule. The permeability of the soft steroids through skin or mucous membrane is similar to or better than the permeability of comparable hard steroids.

References [1] Bodor, N. (1984) Novel approaches to the design of safer drugs: Soft drugs and site-specific chemical delivery systems, Adv. Drug Res. 13, 255-331. [2] Bodor, N. (1988) The application of soft drug approaches to the design of safer corticosteroids. In: E. Christophers, A.M. Kligman, E. Schopf and R.B. Stoughton (Eds.), Topical Corticosteroid Therapy: A Novel Approach to Safer Drug Therapy, Raven Press, New York, pp. 13-25. [3] Bodor, N. (1982) Designing safer drugs based on the soft

T. Loftsson, N. Bodor/Advanced Drug Delivery Reviews 14 (1994) 293-299 drug approach, Trends Pharmacol. Sci. 3, 53-56. [4] Bodor, N. (1982) Soft drugs: Strategies for design of safer drugs. In: J.A. Keverling Buisman (Ed.), Strategy in Drug Research, Elsevier, Amsterdam, pp. 137-164. [5] Bodor, N., Oshiro, Y., Loftsson, T., Katovich, M. and Caldwell, W. (1984) Soft drugs. VI. The application of the inactive metabolite approach for design of soft 13-blockers, Pharm. Res. 1, 12(~125. [6] Bodor, N., Loftsson, T. and Wu, W.M. (1992) Metabolism, distribution and transdermal permeation of a soft corticosteroid, loteprednol etabonate, Pharm. Res. 9, 1275 1278. [7] Bodor, N. (1989) Designing safer ophthalmic drugs. In: H. van der Goot, G. Domany, L. Pallos and H. Timmerman (Eds.), Trends in Med. Chem. '88, Elsevier, Amsterdam, pp. 145 164. [8] Bodor, N. Buris, S. and Buris, L. (1991) Novel soft steroids: Effects on cell growth in vitro and on wound healing in the mouse, Steroids 56, 434-439. [9] Bodor, N., and Wu, W.M. (1992) A comparison of intraocular pressure elevating activity of loteprednol etabonate and dexamethasone in rabbits, Curr. Eye Res. 11, 525 530. [10] Druzgala, P., Hochhaus, G. and Bodor, N. (1991) Soft drugs. 10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: Loteprednol etabonate, J.

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Steroid Biochem. Mol. Biol. 38, 149 154. [11] Reddy, I.K., Wu, W.M. and Bodor, N.S. (1994) Transcorneal delivery and permeability of a soft steroid, loteprednol etabonate, through isolated rabbit cornea, Pharm. Res., in press. [12] Druzgala, P., Wu, W.M. and Bodor, N. (1991) Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes, Curr. Eye Res. 10, 933-937. [13] Hochaus, G., Long-Shui, C., Ratka, A., Druzgala, P., Howes, J., Bodor, N. and Derendorf, H. (1992) Pharmacokinetic evaluation of a new glucocorticoid soft drug: Loteprednol etabonate, J. Pharm. Sci. 81, 1210~1215. [14] Higuchi, T. (1960) Physical chemical analysis of percutaneous absorption process from creams and ointments, J. Soc. Cosmet. Chem. II, 85-97. [15] Loftsson, T. (1982) Experimental and theoretical model for studying simultaneous transport and metabolism of drugs in excised skin, Arch. Pharm. Chem. Sci. Ed. 10, 17-24. [16] Michniak-Mikolajczak, B.B., and Bodor, N. 0985) A study of the penetration of five novel synthetic steroids through hairless mouse skin in vitro, Int. J. Cosmet. Sci. 7, 175-179. [17] Alberth, M., Wu, W.M., Winwood, D. and Bodor, N. (1991) Lipophilicity, solubility and permeability of loteprednol etabonate: A novel, soft-antiinflammatory corticosteroid, J. Biopharm. Sci. 2, 115 125.