Pharmacokinetics Enantiomers and Synovial S. R. Cox,

PhD,

of the R(-) and S(+) of Ibuprofen in the Serum Fluid of Arthritis Patients

E. P. Gall,

MD,

K. K. Forbes

BA,

M. Gresham,

BS, and

G. Goris,

MD

Eight patients with arthritis and knee effusions received 13 doses of a single 800-mg ibuprofen tablet every 8 hours. Serum and synovial fluid samples were obtained after the first and last doses and assayed for the R(-) and S(+) enantiomers of ibuprofen by a stereospecific assay. Since only S(+)-ibuprofen inhibits cyclo-oxygenase, a description of the time course of this isomer in synovial fluid is needed for the development of suitable pharmacodynamic models. The isomers were significantly different with respect to peak concentrations and areas under the concentration-time curves (AUC) in synovial fluid levels. No significant accumulation of either isomer was observed in serum or synovial fluid levels between the first and the last doses. The steady-state concentration of both isomers fluctuated less in synovial fluid than in plasma, and the synovial fluid concentrations of the S(+) isomer were about twice that of the R(-) isomer. The mean synovial albumin concentration was about 60% of the serum albumin concentration, and the steady-state isomer AUC values in synovial fluid were significantly correlated with the corresponding serum values after the differences between the two fluids with respect to albumin concentration were corrected. The authors conclude that binding of the isomers to albumin and the serum-synovial fluid albumin ratio controls the steady-state distribution of the ibuprofen isomers into synovial fluid. The ramifications of these findings in the development of satisfactory concentration-response relationships are discussed.

N

onsteroidal anti-inflammatory drugs (NSAIDs) are the basic therapy available for inflammatory and degenerative arthritis. Much has been learned in recent years about their mechanisms of action in relieving pain and inflammation in joints. Among other mechanisms, the inhibition of prosta-

cumulation and peak levels of these drugs in synovial fluid may lag behind and be lower than those levels in plasma.2 For drugs such as ibuprofen, only the S(+) enantiomeric form inhibits cyclo-oxygenase,3 and it is important to understand the kinetics of this bioactive form of ibuprofen in synovial fluid.

glandin

synthesis,

For

vation, enzymes

and the appear

Although

the

the

prevention

drugs

are

stream, much of their self, and a characterization

NSAIDs portance. sorption,

vary

in synovial Synovial distribution,

with

of neutrophil

stabilization of to be important

protein

fluid

levels

absorbed

action

fluid

cellular in these

may

occurs of the

into

the

be of therapeutic

inflammation.2

The

abmay

ac-

From the Upjohn Company (Drs. Cox, and Goris, Mr. Forbes), Kalamazoo, Michigan, the Department of Internal Medicine (Dr. Gall), The University of Arizona, Tucson, Arizona, and the ABC Laboratories (Mr. Gresham), Columbia, Missouri. Address for reprints: S. R. Cox, Clinical Pharmacokinetics Research Unit, The Upjohn Company, 301 Henrietta Street, Kalamazoo, Ml 49007.

88

#{149} J ClIn Pharmacol

1991;31:88-94

reason, in the

we studied synovial

fluid

the

enantiomers

of patients

of ibu-

with

arthritis.

METHODS itof

im-

reflect and

this

profen

blood

in the joint time-course

levels of NSAIDs and elimination,

and

acti-

lysosomal actions.1

Patients.

A total

of eight

patients,

five

with

active

inflammatory (rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis), and three with degenerative arthritis were enrolled in the study after they gave written, informed consent. The characteristics of these patients are summarized in Table I. All patients had knee effusions that warranted aspiration and several patients had additional stable nonrheumatic diseases. A history and a physical examination were obtained, and a complete blood count, urinalysis, and serum and urine tests of

hepatic

and

renal

function

were

performed.

Patients

IBUPROFEN

IN ARTHRITIS

TABLE Patient

Subject

Age (yr)

1

55

Female

80

2

61

Female

71

I

Demographics Other (Nonarthrltic) Serious, Controlled Disease

Weight (kg)

Sex

PATIENTS

Concurrent

Zinc sulfate furosemide, azathioprine

-

Diabetes,

Medlcations*

Glyburide,

congestive

heart failure

atenolol,

metoclopramide, amitriptyline Auranofin, carisoprodol, diazepam

Psoriasis

3

56

Male

64

4

39

Male

84

-

-

5

79

Male

78

Hypertension, angina,

Cimetidine, ferrous sulfate, hydrochlorothiazide, isorbide dinitrate, theophylline, metoproterenol, potassium

bronchitis

chloride 6

Male

43

67

Hypertension,

cardiac

Promethazine,

arrhythmias

*

7

37

Male

81

Manic-depressive disorder

8

28

Male

76

Psoriasis

Excluding

therapy with gold salts or drugs were enrolled in the been administered at a conmonths. Patients receiving

with long half-lives, from the study,

i.e., but

piroxicam, were patients receiving

NSAIDs with shorter half-lives were enrolled in the study after they completed a 72-hour NSAID-free washout period. During the washout period, the patients were permitted to receive acetaminophen, co-

deine, or propoxyphene for pain. The patients were permitted to continue receiving drug treatment as prescribed by their attending physicians for nonarthritic conditions, but the doses of any concomitant medications were required to be stable during the

study

period.

Synovial

fluid

was

obtained

from

four

tients who met the previously described criteria. These patients had not taken for at least 72 hours before joint aspiration,

samples

were

fen in synovial hour washout

MISCELLANEOUS

Lithium, amitriptyline, oxycodone, sucralfate -

codei ne, and propoxyphene.

acetaminophen,

receiving concomitant other disease-modifying study if these drugs had stant dose for at least 3

NSAIDs excluded

chlorpromazine,

prazosin, methadone, prednisone

used fluid period,

to validate (vide the

the

assay

infra). After remaining

control

pa-

enrollment any NSAIDs and these

for ibupro.

at least a 72eight patients

received

13 doses of a single 800-mg ibuprofen tablet (Motrin, Upjohn, Kalamazoo, MI) every 8 hours. The patients were instructed to take each dose with 6 fluid ounces of water and to record the time of each dose in a diary. Blood (10 mL) was drawn into a vacutainer containing no anticoagulant before the first dose and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after the first dose. The second dose was administered after the 8-hour sample was drawn. Blood samples were obtained at the same times and also at 10 and 12 hours on day 5 after the last dose. Serum was gathered as soon as possible and then frozen until assayed for ibuprofen.

Synovial one knee skin and with 1% fluid ples and

fluid samples were collected from only of each patient. To obtain these samples, underlying tissues were first infiltrated lidocaine, and then I to 2 mL of synovial

was withdrawn using aseptic were drawn at 2 and 8 hours at 2, 4, 6, and 8 hours after

synovial fluid ately after they for protein

and

techniques. Samafter the first dose the last dose. The

samples were centrifuged immediwere drawn and frozen until assayed ibuprofen.

For each

patient,

one

sy-

89

COX

novial

fluid

assayed

sample

for

DACOS nostics,

from

both

total

discrete Hialeah,

each

of the

protein

and

chemistry FL).

analyzer

study

days

was

albumin

by

a

(Coulter

Diag-

Ibuprofen Assays. The serum and synovial fluid samples were assayed for each ibuprofen enantiomer by the capillary gas chromatographic procedure previously described.4 This assay, originally developed fluid with

for the

serum, samples

was from

validated the first

for four

synovial patients.

No interferences were observed from synovial fluid, but only about 80% of either isomer was recovered relative to the plasma values. As a consequence of this low recovery, calibration standards for the synovial

fluid

assay

were

prepared

from

blank

[1]

nKDP

In Equation in the fluid.

1, Pt is the total albumin concentration If drug is extensively bound to albumin (>95%) over the concentration range of interest, then the total drug concentration (C0) will be approximately equal to Cb. If the extent of drug ionization bound),

is equal steady-state

in

and synovial fluid drug concentration concentration sequently CtOtSYn/CIOtS

both drug

fluids, then concentrations

free (unin serum

will be equal. The ratio of total in synovial fluid (C0’y’’) to the

of total drug in described by Equation =

the

serum 2:

(C05)

is con-

[2]

(PSYfl/PS)

If the binding parameters are independent of albumin concentration and identical in both serum and synovial fluid, then the total drug concentration in synovial fluid is described by Equation 3: C tot “#{176}

90

#{149} J Clin Pharmacol

-

C

tot ser (.

1991;31:88-94

t syn I /0

3 should

multiple

classes

be valid of

[3]

even

if binding

independent

steady-state concentrations areas under the concentration 3 is equivalently expressed =

occurs

sites.

to

Since

the

are proportional to the time curves, Equation by Equation 4:

AUC01Ser

[4]

(PSYfl/PSC)

In Equation 4, AUCIO is the steady-state area under the concentration-time curve over a dosage interval. If these assumptions are valid for the ibuprofen isomers, a regression of AUC018” versus the product AUC0 (P1sYfl/P5er) should have a slope of unity and an intercept of zero. Equation 5 follows directly from

Equation

4:

AUCtots/AUCtotrSYfl

Theory. For simplicity, drug binding to albumin is assumed to occur at one class of independent sites with association constant K and with a total number of sites n. Drug is assumed to bind only to albumin in both serum and synovial fluid, although the binding parameters do not have to be identical in both fluids. If the free drug concentration (C1) is sufficiently low, i.e., KC1 < .1, then the bound drug concentration (Cb) may be approximately given by Equation 1: =

Equation

synovial

fluid rather than from serum. The precision of the assay for the ibuprofen enantiomers in synovial fluid, as indicated by relative standard deviations, was less than 12% for enantiomer concentrations of I to 45 1zg/mL. Accuracy of the assay, as determined from the mean recovery of quality control standards, ranged from 93% to 100% over this same concentration range.

Gb

ET AL

In Equation

uration 5, the

AUCtotsser/AUCtotrser

=

the subscripts

5,

r or s denote

of the ibuprofen isomer. ratio of the steady-state

Based AUG

isomers in synovial fluid should the ratio of the isomers in serum. Data

Analysis.

vial fluid dose were trapezoidal tions

areas

under

the

than

.5 1zg/mL

fluid

config-

be estimable

the

serum

concentration-time curves calculated through 8 hours rule. In these calculations, synovial

the

on Equation values of the

from

and

after

syno-

the

last

(AUCO8)

by

concentra-

were assumed to be zero, concentrations at the beginning of the last dosing interval were assumed to be equal to the concentrations at 8 hours, the end of the steady-state dosing interval. The terminal disposition rate constant (Xj for each isomer was calculated from a log-linear regression of the serum concentration-time data apparently within the terminal disposition phase after the last dose. The maximum concentration (Cmax) after the last dose, the time of its occurrence (Tmax), and the ratio of maximum to

and

less

The

[5]

minimum concentrations dosing interval (Cmax/Cmjn) enantiomers rameters lated for

in serum

and

Tmax,

and

during were

the steady-state tabulated for both

in synovial fluid. The paAUG0_8 were also calcuboth enantiomers in serum after the first dose. Paired t tests were used to test the significance of the differences: 1) between isomers within a matrix (either serum or synovial fluid) with respect to Cmax,

the steady-state tween matrices parameters for

pharmacokinetic with respect each isomer,

day 5 serum isomer, and

between

pharmacokinetic 4)

parameters, 2) beto the pharmacokinetic 3) between day I and parameters

day

1 and

day

for

each

5 synovial

fluid concentrations of each isomer at both the 2and the 8-hour time points. Bonferroni corrections were used in these tests to maintain an overall value of a at .05. Regression analysis was used to evaluate correlations both among the isomers with respect to

IBUPROFEN

IN ARTHRITIS

PATIENTS

presented in Figure 1. Pharmacokinetic parameters for both isomers are listed in Tables II and III. The values for synovial fluid AUG08 were calculated by assuming that the observed concentrations at the end of the steady-state dosing interval were equal to the concentrations at the beginning of the interval.

40 E

This was done to limit the samples that were obtained

Ibuprofen both serum

j10

2 0

1

2

lime Identity

r-plssma

-

4

3 After

Oru

5

5

Administration

r-synoviat

Figure 1. Average concentrations plasma and synovial fluid. Error the mean.

-

- -

7

s-plumS

-

fluid

to only a minor extent in fluid over the time course

as evidenced by the lack of significant between days I and 5 regarding serum Cmax serum AUCO8, and synovial fluid concentrations at 2 and 8 hours. The mean serum AUCO8 values for both isomers on day 5 tended to be about 17% higher than those from day 1, and this small

s-syiioviat

-

of synovial each patient.

of the study, differences

0

(hours) -

accumulated and synovial

number from

difference cumulation

of the ibuprofen enantiomers in bars indicate ±1 standard error of

was consistent with that was predicted

These results support conditions prevailed

the steady-state from the day

acdata.

5

a contention that steady-state on day 5 of the study.

pharmacokinetic parameters within a fluid and also among fluids with respect to isomer pharmacokinetic parameters. Ratios of the steady-state concentrations of the isomers in synovial fluid and serum

The concentration-time differed significantly fluid. The Gmax values

were

in serum were about 40% of the values in synovial fluid. Also, the fluctuations between the maximum and minimum ibuprofen concentrations were much less in synovial fluid than in serum. As shown in Figure 1, serum and synovial fluid concentrations of each isomer were different at 2 hours but similar at times 4 hours. The average (±SD) steady-state sy-

compared

by a paired

in serum

t-test.

RESULTS Average

concentration

ibuprofen

isomers

versus in

serum

time and

curves

for both

synovial

fluid

are

TABLE Summary

of Plasma

than

profiles of both isomers between serum and synovial were about three times higher

in synovial

Subject

(hr)

C (Mg/mi)

AUC

Pharmacokinetic

(mL/mln/kg)

0.29

5.9

0.75

1.5

27

103

2.7

1.2

2.0

17

70

0.27

1.2

0.5

33

78

0.42

(hr’)

1.5

27

112

2

2.5

13

78

0.40

3

0.5

33

87

0.38

21

4

0.5

23

73

0.42

16

5

1.0

29

107

0.32

6

1.5

36

113

0.30

7

1.0

30

92

0.33

8

2.0

21

82

0.33

8.8

Mean

1.3 ± 0.7

26

93 ± 16

0.35 ± 0.05

9.2 ± 5.7

*

SD

± 7

Minim urn ratio s ince the C,,,, was below

MISCELLANEOUS

the limit

values

Tmax

R(-).lbuprofen

1

±

the

Parameters

C,/ C,,.,,,

X,

(Mg hr/mL)

and

II

S(+)-lbuprofen T

fluid,

CI,,.

C,..,

T

(hr)

(Mg/mi)

AUC0

X

(Mg hr/mi)

(hr1) 0.32

C,,,,,,/ C,.,,,

CI., (mi/mitt/kg)

17

0.81

5.9

1.3

33

1.4

1.1

0.5

21

50

0.57

>42*

1.6

0.81

1.0

28

84

0.39

12

1.0

10

0.87

1.0

16

36

0.16

15

2.8

12

0.89

1.0

22

41

0.37

42

2.0

1.1

1.0

25

75

0.62

41

1.2

1.1 ± 0.5

24 ± 6

67

0.39 ± 0.15

8.3

of qua ntitation,

1.0 ± 0.2 0.5 Mg/rnL.

The overall

±

23

me an value was calculated

26 ± 15

±

1.5 0.6

with a ratio of 42 for this subject.

91

COX

ET AL

TABLE Summary

of Synovial

III

Fluid Pharmacokinetic

Parameters

S(+)-lbuprofen

Subject

T,,..,,

1 2 3

4

4 5

6

7 8 ± SD

Mean *

Minimum

ratio since

for

R(-)-lbuprofen AUC

20

C,,,.,,/Cmt,,

1,..,,,,

106

2.4

4

2.1

4

5.6

28

3.0 2.6

2 2

16 5.7

84 25

4

4.8

30

4 4 2

8.9 15 11 11 ± 5

54 78 67

3.1 5.7 2.1 1.7 2.5 2.0

2 2 2 4 4 2

11 3.7 3.6 2.7 5.1 6.2

58 12 19 15 29 37

3.3 >74* 3.0 2.7 3.2 2.7

2.7 ± 1.3

3.0 ± 1.1

6.4 ± 3.8

32 ± 18

the C,,

value was below

61 ± 28

the limit of quantitation,

0.5 Mg/mL.

ratio, was .53 its optical

The overall

with >

were

observed

of either

ing albumin-normalized slopes not significantly 2, 3). Other correlations

among

isomer

and

the the

serum

AUCO8

different

from

were

also

synovial

correspond-

values, unity

observed

with (Figures

between

mean

the synovial centrations = .62) and

Serum and synovial fluid levels differed significantly with respect to albumin concentration, with mean (±SD) values of 3.9 ± 0.5 and 2.3 ± 0.6 g/dL, respectively. As predicted by the model, significant

13

Cma,,/Cmtn

44

antipode.

AUCO#{216}values

AUC

8.1

to serum ibuprofen concentration as the ratio of AUCQ8 values, the R-isomer and .66 ± .27 for

correlations

Cm,,,,

4

3.25 ± 1.0

novial fluid calculated ± .14

C,,,,,,

61

value was calculated

3.5 ± 1.6

with a ratio of 7.4 for this subject.

and albumin-normalized serum conof S(+)-ibuprofen at 8 hours (P < .03, r2 between the isomers in synovial fluid to both Gmax and AUCO8 (P < .006, r2

respect

.74).

The

values

for

X5 were

calculated

for

drug

in

serum on day 5 alone, because only then were a sufficient number of time points for reliable lations. No difference was observed between isomers with respect to X, and the harmonic

there calcuthe mean

half-lives

and

hours, respect

of R-

and

respectively. to the other

S-ibuprofen The serum

were

isomers did pharmacokinetic

not

1.8

2

differ with parame-

70 E

#{163}

0

SO

0 0

2

50

0

I

p a 0

I

0 0

20

30

40

50

00

Serum S(+).ibeprots

71

00

50

100

AUC,.,, (mci hr/el)

2. Plot of S(+)-ibuprofen steady-state AUCOS values: Synovial AUCO8 versus albumin-normalized serum AUC08. The line is from a statistically significant linear regression (P < .004). Regression results: r2 = .75, slope (mean ± SE) = 1.1 ± .2, intercept not significantly different from zero. Figure

92

#{149} J Clln Pharmacol

1991;31:88-94

10

20

30

40

Serum R(-)-ihepmten

50

60 AUC,

70

00

90

(mcg Ir/mi)

Figure 3. Plot of R(-)-ibuprofen steady-state AUC08 values: Synovial AUCOS versus albumin-normalized serum AUCOS. The line is from a statistically significant linear regression (P < .00 1). Regression results: r2 = .85, slope (mean ± SE) = 0.77 ± .12, intercept not significantly different from zero.

IBUPROFEN

IN ARTHRITIS

ters except that the serum AUG08 values for 5-ibuprofen tended to be larger than those of R-ibuprofen (.05

Pharmacokinetics of the R(-) and S(+) enantiomers of ibuprofen in the serum and synovial fluid of arthritis patients.

Eight patients with arthritis and knee effusions received 13 doses of a single 800-mg ibuprofen tablet every 8 hours. Serum and synovial fluid samples...
1MB Sizes 0 Downloads 0 Views