Tissue-plasma distribution of inhaled glucocortocoids: Comparison of human in vitro and in vivo data

Relating

to Invited Lecture 4-Pharmacokinetics

& Metabolism

The ethyl

present

testes)

T~,sue slices have the potential to determine in vifro tissue to unbound drug in plasma partltion coefficients (I$,) that are more consistent with in viva measurements than homogenates because the cellular architecture of the ussue predommantly remains intact. We have undertaken some fundamental studies wth tissue slices to determme the possibilmes and lmutations of the technique. One study mvestlgated the behawour and effects of albumin on the distribution of a congenenc senes of 5-alkyl..Sethyl barbitunc acid denvatives (BAD). The in vitro dlffislon of albumin from tissues was determined by mtravenously dosing radiolabelled (“‘I) human serum albumin to rats, taking tissue samples 48 hours later and incubating them in a physiologwal buffer. The level of radioactivity was determined prior to and at the end of the incubation. The amount of albumin lost from the tissue at eqwhbrium (2 to 3 hours) varied from 50 to >95% depending on the tissue to buffer volume ratlo and the specific tissue. The in vitro chstribution of BAD were determined by incubatmg fresh rat tissue wth BAD in a protein free physiological buffer for 2 hours. BAD concentrations were determmed in both tissue and buffer at the end of the incubation. For the n-nonyl BAD the 5 in muscle was estimated at around 70. assuming that all the drug remaining in buffer was not bound to protems The n-nonyl BAD however is 99% bound to proteins in plasma. Based on the relative amounts of albumm and n-nonyl BAD in the buffer the real Kpy in muscle, assuming non-saturable binding, would be around 7000! Even if the binding was saturable, the effecnve I& would be substantially greater than that origmally measured.

study exammed

barbwnc

stomach,

acids

pancreas, after

ments

ters have

r

been

tissues

gut.

testes

of the homologues optlmlsed

parWon

to

rats

ratlo).

(see table,

lung,

skin,

model and brain,

(Cl=methyl. Kpu

bone,

has

been

compartparame-

tissue-to-unbound

concentration-time

Cl

c2

-K -

c4

c5

C6

1 04

1 69

2 55

342

6 70

LIVER

2 75

3 a7

341

4 94

6 60

1530

KIDNEY

125

186

4 55

7 33

5 97

11 57

STOMACH

0 26

0 30

0 72

2 17

3 22

1627

PANCREAS

0 32

0 38

0 69

1 46

2 54

9 06

SPLEEN

0 58

0 00

1 33

2 17

2 89

645

GUT

060

0 72

1 20

3 09

3 95

12 22

MUSCLE

060

0 a5

161

2 20

4 03

11 28

ADIPOSE

0 35

0 75

1 54

2 98

7 20

66 22 1467

SKIN

1 12

1 25

1 80

2 28

2 30

BONE

0 98

0 65

1 50

1 63

1 00

HEART

0 55

0 72

1 24

3 06

4 84

BRAIN

0 60

0 76

1 42

2 57

2 51

12 a3

TESTES

069

0 79

163

2 59

3 95 -

-

PSsw

0 0.2:

oo80

xz

0450

1500

0 OEX

0 130

3 200

0 690

1950

45 00

0 ll(

0 210

S 240

4 270

3 620

70 2

0564 -

3 294 L

0 194 -

elusions

are drawn

and the parWon

permeability

llmltabon

coeficlents

of the tissues

for some of the tissues

12 67 8 22 7 00

0 05 1118 between the hpophiliclty

f0 Nrthe relationship

homologues

data

Kpu

0 61

0 52

constructed.

). the model

LUNG

CLren

bram

whole-body

etc.

Param

CLlnt

kidney.

heart.

to be well-stirred

extravascular

usmg the expenmental

TlSSUd

PSTESTES

5-n-alkyl-5-

liver.

A 16 compartment

of the

The posslblllty

of a

IS dlscussed

For the climcal use of inhaled glucocortlcads

The aims of this study were to develop a specific assay for midazolam in tissues, to determine the steady state tissue:blood (k& tissue:plasma (kJ and tissue:plasma water (11) partition coefficients of midazolam in all major organs and tissues in the rat and to predict the volume of distribution at steady state (VA of midazolam in rats and humans. The drug was infused for 7-8 h into conscious rats. Blood, plasma and tissue concentrations of midazolam at the end of the infusion and the unbound 6action in plasma (fJ were determined by gas-liquid chromatography with electron capture detection. Apparent volumes of distribution (V,) in all tissues were calculated as k.. fU. (physiological volume) and V, as the sum of V,. Conventional pharmacokinetic parameters of midazolam were determined in five women given iv midazolam before surgery. In the rats, the k, in 12 tissues ranged between 1.3 (in muscle) and 9.0 (in adipose tissue). Since the mean f. of midazolam in rat plasma was 7.9%, k, ranged correspondingly between 16and115.ThecalculatedV,ina250gratwas2.15Ukg,infair agreement with indirect determinations in the literature. The measured mean V, and fUin the five women were 1.28 L./kg and 2.4%. respectively. The V, calculated from the k,, values was I .37 ykg. Dishibution to adipose tissue accounted for 71% of this Vd.,. The findings provide a basis for physiological pharmacokinetic modeling of midazolam in rats and humans.

of seven

blood,

adipose,

pharmacokinetvz except

kmebcs

(artenal

muscle,

admmlstratlon

based

SC)1

,042)

the dlstrlbutlon

14

spleen,

all the tissues,

For each

plasma

I”

I v. bolus

physiologically assummg

(Pl.OOl-PI

I” asthma I, II not only the rate

and extent of uptake inlo the lung and the affmlty to the glucocortlcold receptor which detetmmes lvgh efficacy, but also the relcntmn m amvays. since thts means prolonged aniimflammatory

actwn and low plasma levels. The

uptake into human lung tissue was dewmmed

m wtro for becomethasone-

17.21 -dtproptonate (BDP) and 11s actwe metabohte beclomethasone-17.monoproptonate (17.BMP), flumsohde.

Tissue

fluticasone-I 7-propmnate (FP), budesomde and

pwces were mcubated I” buffered CC solutions.

nssue was fastest and highest concentratws CCs: FP. BDP and 17.BMP. were highest for BDP.

Uptake anto

were found for the more hpophdlc

The absolute amounts of CCs retamed ,n t,ssue

17.EIMP and FP. The concentratmn of FP was more than

twice as high as for budesomde and flunlsollde

The dastrlbutaon of Inhaled FP

between central and peripheral human lung IISSW and blood plasma was subsequently

determmed 8” I’IYO In 14 patients due for lung resectmn surgery,

a stngle 1.0 mg dose of FP was whaled at varymg twne pants pre-operat~vly. FP concentrations

m tasue and plasma samples were determlned by RIA

FP

concentratmns I” central lung ttssue were approximately three to four rimes higher than in peripheral lung tissue concentratmns, which an turn. exceeded those found m blood plasma by IO-fold. Peripheral

lung tissue concentral~ons

of FP exceeded the concentrations found for budesomde m a similar study by 2.fold and conversely, plasma concentrations

of budesonide were higher than

for FP (Van den Bosch )MM et al. Biopharm Drug Disp 1993,

14: 455.459

The results of this study demonstrate a high m vrrro! ,n YWO correlation of tarsue-plasma dastrlbutlon for glucocortlcolds

)