ENDOCRINE

Pharmacokinetics Hartmut

and Oral of Hydrocortisone

Derendorf,

Carsten

PhD,

MOllmann,

Helmut

FCP,

Sabine

Tunn,

PhD,

AGENTS

Bioavailability

MOllmann, MD,

METABOLISM

MD, and

Jurgen

Michael

Barth, Krieg,

MD, MD

The

pharmacokinetics of 20mg hydrocortisone were studied after IV and oral administration. Endogenous hydrocortisone was suppressed by dexamethasone administration. Hydrocortisone concentrations were measured in plasma and saliva. After N administration, hydrocortisone was eliminated with a total body clearance of 18 L/hr and a half-life of 1.7 hr. The volume of distribution was 34 L. Oral bioavailability averaged 96%. Absorption was rapid, achieving maximum hydrocortisone levels of 300 ng/mL after 1 hour. Saliva levels were not proportional to plasma levels, but could be shown to reflect free, non-protein bound hydrocortisone concentrations in plasma.

A

lthough hydrocortisone was designated by the U.S. Food and Drug Administration as a drug whose different brands and dosage forms should be examined for bioequivalence,1 few studies have been published to address its absolute bioavailability. Intravenous pharmacokinetic studies have been performed using hydrocortisone hemisuccinate2 as a water-soluble pro-drug. However, after IV hemisuccinate administration of other corticosteroids, substantial amounts of the pro-drug could be found in the urine34 making it a less than optimum standard for an assessment of absolute bioavailability. Relative bioavailability studies have been described for tablets5 and suspensions.6 The presented studies determined the absolute bioavailability of hydrocortisone using an alcoholic solution of hydrocortisone as the IV reference. Previous studies have indicated a dose non-linearity in the pharmacokinetics of hydrocortisone with increased total body clearances at higher doses.2 This was shown to be related to concentration-dependent changes in the binding of hydrocortisone to plasma proteins. In other studies, we have shown that saliva levels of methylprednisolone and prednisolone were identical to free, non-protein bound concentrations in plasma.47 Methylprednisolone plasma/saliva ratios were constant during the post-

distribution phase indicating linear protein binding, whereas for prednisolone, plasma/saliva ratios changed with concentration. Thus our second goal of the presented study was to evaluate the concentration dependence of protein binding of hydrocortisone and its effect on plasma/saliva ratios for this drug.

From the Department

Non-Compartmental

of Pharmaceutics,

University

of

Florida,

Gaines-

and the Medical Clinic, University of Bochum, West Germany (Drs. H. MOllmann, Barth, Tunn, and Krieg). Address for reprints: Hartmut Derendorf, PhD, Box J-494, ville,

Florida

College

(Dr.

Derendorf

of Pharmacy,

J Clln Pharmacol

METHODS The oral

pharmacokinetics administration

Hoechst#{174})

were

of hydrocortisone of a 20-mg dose determined

in

eight

after IV and (Hydrocortisone healthy

male

subjects. The average age of the subjects was 28 ± 9 years, the average weight was 74 ± 6 kg. Endogenous hydrocortisone production was suppressed to less than 10 ng/mL by oral administration of 4 mg dexamethasone at 10 PM the day before the study. Blood samples were taken immediately before drug administration and after 10, 20, 30, 40, 60, 90, 120, and 150 minutes as well as after 3, 4, 5, 6, 8, 10, 12, 14, and 24 hours. Saliva was collected after 10, 20, 30, and 60 minutes as well as after 2, 4, 6, and 8 hours. Hydrocortisone concentrations were measured by radioimmunoassay in serum and saliva and corrected for the individual pre-dose levels. The data was subjected to compartmental and non-compartmental pharmacokinetic analysis. Pharmacokinetic

Analysis

and C. MOllmann);

University

1991;31:473-476

of Florida,

Gainesville,

FL 32610.

The area under the plasma curve (AUC) was calculated rule. The total body clearance

concentration-time using the trapezoidal (CL) was calculated

as

473

DERENDORF

dose (20 mg) divided by AUC. Mean residence time (MRT) was calculated as area under the first moment curve (AUMC) divided by area under the curve (AUC). AUMC was determined using a plot of plasma concentration times time (Cp. t) versus time and calculation of its area under the curve calculated by the trapezoidal rule. The volume of distribution at steady state (Vd8J was determined as the product of total body clearance and mean residence time (CL. MRT). The bioavailability (BA) of hydrocortisone after oral administration was calculated as AUC /AUC1 100. The mean absorption time (MAf of hydrocortisone after oral administration was calculated as MRT MRTV. The maximum plasma concentration max) is the experimental value with the highest plasma concentration. The time of the maximum plasma concentration (tmaJ is the experimental data point when Cmax was measured. -

Compartmental

Pharmacokinetic

Analysis

Compartmental pharmacokinetic analysis formed using the non-linear regression RSTRIP.8 Best results were obtained with a partment body model for the IV data, whereas oral data, a one-compartment body model factory.

was perprogram two-comfor the was satis-

Compartmental analysis of intravenous data. The data was fitted to the biexponential equation Cp = a eat + b. et. From the results, the following pharmacokinetic parameters were derived: Half-life (t112) was calculated as ln 2/f. Area under the curve (AUC) was calculated as a/a + b/j3. Total body clearance (CL) was calculated as dose/AUC. Mean residence time (MRT) was calculated as area under the first moment curve* (AUC). AUMC was determined as a/a2 + b/$2. The volume of distribution at steady state (Vd) was determined as the product of total body clearance and mean residence time (Cl. MRT). The volume of distribution of the central compartment (VJ was calculated as dose/(a + b). The volume of distribution during the elimination phase (Vdaroa) was calculated as CL/.

ET AL

(AUMC) divided by area under the AUMC was determined as b. (1/k02 1/k02). The mean absorption time (MAT) of hydrocortisone after oral administration was calculated as MRT MRTV. The maximum plasma concentration ma,() is the fitted plasma concentration at the time of the maximum plasma concentration, and tmax was calculated as ln(k8/kj/(k8-kj. moment

curve

curve

(AUC).

-

-

RESULTS Pharmacokinetics

of Hydrocortisone

After

IV

Administration After IV administration, hydrocortisone shows the classic biexponential plasma concentration profile (Figure 1). The average pharmacokinetic parameters are listed in the Table. The total body clearance is 18.2 ± 4.2 L/hr, the terminal half is 1.7 ± .5 hr. The mean residence time is 1.9 ± .4 hr. The volume of distribution at steady state is 34 ± 5 L. These parameters were determined by non-compartmental analysis. However, there is little difference to the results that were obtained from compartmental analysis with a total body clearance of 18.0 ±4.3 L/hr, a mean residence time of 2.3 ± .6 hr, and a Vd of 40 ± 8 L. Other parameters derived from compartmental analysis are V of 24 ± 5 L and Vd000 of 41 ± 9 L. Pharmacokinetics Administration

of Hydrocortisone

After

After oral administration hydrocortisone low the classic one-compartment body

levels model

Oral

fol(Fig-

1000

n

E

100

a, C

0

10

Compartmental analysis of oral data. The data was fitted to the biexponential equation Cp = b . (et et). From the results, the following pharmacokinetic parameters were derived: Half-life (t112) was calculated as In 2/k0. Area under the curve (AUC) was calculated as b (1/ke 1/k0). Mean residence time (MRT) was calculated as area under the first -

02

4

6 time

8

10

12

[hours]

-

Figure

*

474

(AUMC)

divided

by area

#{149} J Clln Pharmacol

under

the curve.

1991:31:473-476

1. Plasma intravenous subjects. after

concentration (mean ± SD) of hydrocortisone (#{149}1 and oral (0) administration of 20mg to eight

HYDROCORTISONE

± .9 hr1 and .41 ± .11 hr1.

1.4

TABLE

Pharmacokinetic

Parameters

(Means

Hydrocortlsone After Intravenous Oral AdmInistration

1163 (277) 18.2 (4.2) 33.7 (4.6) 1.9 (.4) -

-

and

Analysis P0

1094

(266) -

3.2 (.5) 1.2 (.5) 305 (57)

1.2 (.4)

-

(19.6)

95.9

-

Compartmental

Analysis a [ng/mL] b [ng/mL] a [h’]

430 439 13.1 .445

fi [h1] k0[h’] t112 [hr] AUC [ng.hr/mL] CL [L/hr] Vd [Li MRT [hr]

VC[L}

(169) (139) (11.6) (.096)

1.66 (.48) 1175 (285) 18.0 (4.3) 39.9 (7.8) 2.3 (.6) 23.9 (4.8) 41.4

Vd*r.a [LI MAT [hi

-

C,,00 [ng/mL]

-

t,

-

[hr]

BA[%]

(1342) -

1.82 (.52) 1162 (308)

-

-

3.6 (.5)

1.3(5) 1.40 (.90) 258 (70) 1.4 (.3) 100.5 (21.1)

ure 1). The average pharmacokinetic parameters are listed in the Table. The terminal half- life is 1.8 ± 0.5 hr, hence identical to that after IV administration. The absolute bioavailability averages 96 ± 20% indicating complete oral absorption. The mean residence time is 3.2 ± .5 hr, which is composed of the MAT (1.2 ± .5 hr) and the MRT after IV administration (1.9 ± .4). Maximum hydrocortisone levels of 305 ± 57 ng/mL were observed after 1.2 ± .4 hr. These parameters were determined by non-compartmental analysis. However, there is little difference to the results obtained from compartmental analysis with an absolute bioavailability of 101 ± 21%, a mean residence time of 3.6 ± .5 hr and a MAT of 1.3 ± .5 hr. Maximum model predicted hydrocortisone levels of 258 ± 70 ng/mL were calculated for an average tmax at 1.4 ± .3 hr. Other parameters derived from compartmental analysis are the absorption rate constant k0 of

ENDOCRINE

METABOLISM

AGENTS

rate

constant

of

ke

of Saliva

Levels

of Hydrocortisone

Saliva levels of hydrocortisone were measured simultaneously with the plasma levels. The results indicate that hydrocortisone saliva levels are not proportional to plasma levels. For high concentrations, the saliva/plasma ratio was higher than for low concentrations. It has been shown4’7 that during the elimination phase, saliva levels are a good estimate for the free, non-protein bound concentration of corticosteroids in plasma. This assumption was used to calculate the degree of plasma protein binding at various concentrations. Figure 2 shows the relationship between the fraction bound to plasma protein and the measured saliva levels. The results are consistent with in vitro studies on the plasma protein binding of hydrocortisone,9 which had shown a decrease in protein binding from 95 to 75% in a concentration range up to 200 ng/mL. DISCUSSION

-

(9.1) -

K [h]

-

1229

.413(.114)

-

elimination

and SD) for

IV

Non-Compartmental Analysis AUC [ng’ h/rn L] CL [L/hr] Vd[L] MRT [hr] MAT [hr] Cn,ax [ng/mL] t,fla, [hr] BA [%]

the

The pharmacokinetic parameters for the IV study are consistent with those reported after IV administration of the hemisuccinate ester.2 Although both studies were done in different subjects, this indicates an efficient bioconversion of the hemisuccinate ester to its active alcohol.

Figure

2. Relationship between measured saliva levels (0) and fracbound to plasma proteins calculated from plasma samples drawn at identical times in the post-distribution phase after intravenous administration. tion

475

DERENDORF

After oral completely availability centrations the 225-285

administration, hydrocortisone was absorbed, and the mean absolute biowas 96%. The observed maximum conof 305 ng/mL after 1.2 hours agree with ng/mL after 1.0 to 1.4 hours using four different tablets5 and the 263-311 ng/mL after 0.7 to 0.9 hours using suspensions.5’6 The saliva level data imply that saliva may be a good indicator for free, non-protein bound concentrations for corticosteroids in plasma. Whereas methylprednisolone had shown constant plasma/ saliva ratios,7 hydrocortisone behaves more like prednisolone4 since the ratio of plasma/saliva is higher for low concentrations than for high concentrations. These results can be explained by the nonlinear protein binding of prednisolone and hydrocortisone in comparison to the linear binding of methylprednisolone. Hydrocortisone binds to both albumin and corticoid-binding globulin (CBG). The binding to albumin is not saturable in the concentration range of interest, whereas the binding to CBG is saturable in the therapeutic range. An increase in the free fraction in plasma results in an increase in total body clearance with dose, and hence, in less than dose proportional

with

476

increasing

increases

in

steady-state

doses.

#{149} J Clin Pharmacol

1991;31:473-476

plasma

levels

ET

AL

REFERENCES 1. Fed.

Register.

1976;

42:1624.

2. Toothaker RD, Welling PC: Effect of dose size on the pharmacokinetics of intravenous hydrocortisone during endogenous hydrocortisone suppression. I Pharmacokinet Biopharm 1982;10:147156. 3. MOllmann H, Rohdewald P. Barth J, MOllmann C, Verho Derendorf H: Comparative Pharmacokinetics of methylprednisolone phosphate and hemisuccinate in high doses. Pharm 1988;8;509-513. 4. Derendorf H, Rohdewald Neveling D: Pharmacokinetics prednisolone hemisuccinate. 432.

P, MOllmann H, Rehder J, Barth of prednisolone after high doses Biopharm Drug Disp 1985;6:423-

M, Res J, of

5. Patel RB, Rogge MC, Selen A, Goehl TJ, Shah VP, Prasad VK, Welling PG: Bioavailability of hydrocortisone from commercial 20 mg tablets. J Pharm Sci 1984;73:9&4-966. 6. Toothaker RD, Craig WA, Welling PC: Effect of dose size on the pharmacokinetics of oral hydrocortisone suspension. J Pharm Sd 1982;71:1182-1185.

7. H. MOllmann, Pharmacokinetics lone phosphate. 8. RSTRIP, tion (Vers. 84121.

P. Rohdewald, J. Barth, M. Verha, H. Derendorf: and dose linearity testing of methylpredriisoBiopharm Drug Disp 1989;10:453-464.

Exponential 4.0). MicroMath

curve stripping and Scientific Software,

parameter Salt Lake

estimaCity, UT

9. Cope CL: Protein binding of adrenocortical sterQids, in, Adrenal Steroids and Disease, 2nd Edition, Philadelphia: J.B. Lippincott, 1972;59-61.