a pharmacodynamic and pharmacokinetic study with vedaprofen in an equine model of acute nonimmune...

INTRODUCTION

Vedaprofen (dL-2-(4 cyclohexyl-1-naphthenyl) propanoic acid) is

an NSAID of the 2-arylpropionic acid class. It is licensed for use

in the dog and horse. Structurally it is related to ketoprofen and

carprofen and, like these other 2-arylpropionic acids, it contains

a single asymmetric carbon atom and therefore exists as R(±)

and S(+) enantiomers (Fig. 1). Like other drugs of this class, the

S(+) enantiomer is generally regarded as the eutomer and the

R(±)-antipode is regarded as the distomer, although for some

actions of some profens the two enantiomers are equipotent

(Hutt & Caldwell, 1983; Caldwell et al., 1988; McCormack &

Brune, 1991; Evans, 1992; Suesa et al., 1993; Villanueva et al.,

1993). It should be noted also that for vedaprofen the R(±) and

S(+) enantiomers were equipotent in inhibiting PGF2a induced

contractions of the rat fundus strip (ex vivo model), whereas

there was a 70-fold difference in inhibiting cyclo-oxygenase

using an in vitro test with cyclo-oxygenase from bovine seminal

vesicles (IC50 values S(+), R(±) and racemate: 1.6, 111 and 3.3

mM, respectively) (unpublished data).

It is becoming increasingly clear that, whilst all NSAIDs have

several properties in common, including analgesic, anti-inflam-

matory, antipyretic and anti-endotoxic actions, there can be

significant pharmacokinetic and pharmacodynamic differ-

ences between them and between the enantiomers of the

#1999 Blackwell Science Ltd 96

J. vet. Pharmacol. Therap. 22, 96±106, 1999. PHARMACODYNAMICS

A pharmacodynamic and pharmacokinetic study with vedaprofen in an

equine model of acute nonimmune inflammation

Lees, P., May, S. A., Hoeijmakers, M., Coert, A., Rens, P. V. A pharmacodynamic

and pharmacokinetic study with vedaprofen in an equine model of acute

nonimmune inflammation. J. vet. Pharmacol. Therap. 22, 96±106.

The pharmacodynamics and enantioselective pharmacokinetics of vedaprofen

were studied in six ponies in a two period cross-over study, in which a mild

acute inflammatory reaction was induced by carrageenan soaked sponges

implanted subcutaneously in the neck. Vedaprofen, administered intravenously

at a dosage of 1 mg/kg, produced significant and prolonged inhibition of ex vivo

serum thromboxane B2 (TXB2) synthesis and short-lived inhibition of exudate

prostaglandin E2 (PGE2) and TXB2 synthesis. Vedaprofen also partially inhibited

oedematous swelling and leucocyte infiltration into exudate. Vedaprofen dis-

played enantioselective pharmacokinetics, plasma concentrations of the R(±)

enantiomer exceeding those of S(+) vedaprofen. The plasma concentration

ratio, R:S, increased from 69: 31 at 5 min to 96: 4 at 3 h and plasma mean AUC

values were 7524 and 1639 ng.h/mL, respectively. Volume of distribution was

greater for S(+) vedaprofen, whilst elimination half-life (t�b) and mean

residence time were greater for R(±) vedaprofen. The penetration of vedaprofen

into inflammatory exudate was also enantioselective. For R(±) and S(+) veda-

profen maximum concentration (Cmax) values were 2950 and 1534 ng/mL,

respectively, and corresponding AUC values were 9755 and 4400 ng.h/mL.

Vedaprofen was highly protein bound (greater than 99%) in both plasma and

exudate. The significance of these data for the therapeutic use of vedaprofen

is discussed.

(Paper received 23 February 1998; accepted for publication 21 September 1998)

Peter Lees, Royal Veterinary College, University of London, Hawkshead Campus,

North Mymms, Hatfield, Herts., AL9 7TA, UK.

P. LEES*

S. A. MAY*

M. HOEIJMAKERS{

A. COERT{ &

P. V. RENS{

*Royal Veterinary College, University of

London, Hawkshead Campus, North

Mymms, Hatfield, Herts., AL9 7TA, UK;

{Intervet International B.V., PO Box 31,

5830, Boxmeer, The Netherlands

Ahed

Bhed

Ched

Dhed

Ref marker

Fig marker

Table mar-

ker

Ref endRef start

Fig. 1. Chemical structure of vedaprofen. Asterisk denotes chiral centre.

Paper 173 Disc

2-arylpropionate subgroup. For example, in the horse the

elimination half-lives (t�b) of both ketoprofen enantiomers are

short, whilst those of carprofen are long. Moreover, following

administration of the racemates, S(+) ketoprofen and R(±)

carprofen predominate in biological fluids, such as plasma,

transudate and exudate (Delatour et al., 1993; Jaussaud et al.,

1993; Lees et al., 1994a, b; Landoni & Lees, 1995, 1996a, b). In

addition, at clinical dosages ketoprofen is a potent inhibitor of

cyclo-oxygenase (COX), the enzyme which generates an

important group of inflammatory mediators, the prostanoids

such as prostaglandin E2 (PGE2). Carprofen, on the other hand, is

a weak inhibitor of this enzyme at clinically effective dosages

(Lees et al., 1991a, 1994a; Suesa et al., 1993; McKellar et al.,

1994a; Owens et al., 1994; Short et al., 1994; Landoni & Lees,

1995, 1996a).

Vedaprofen as the racemic mixture has been developed for use

in equine and canine medicine. Only preliminary reports on the

pharmacodynamics and pharmacokinetics of the drug have been

presented in these species (Hoeijmakers et al., 1994a, b; Lees et

al., 1994b). As there are no detailed reports on the pharmaco-

kinetics and pharmacodynamics of vedaprofen in the horse, this

study was undertaken with the objectives of establishing for rac-

vedaprofen administered intravenously at a dosage of 1 mg/kg

(total drug): (a) the anti-inflammatory effects against a mild

acute inflammatory reaction; (b) the time course of in vivo

inhibition of synthesis of PGE2 and TXB2 in inflam-matory

exudate and ex vivo inhibition of synthesis of TXB2 in serum; and

(c) the pharmacokinetics of vedaprofen enantiomers in plasma

and their penetration into inflammatory exudate.

MATERIALS AND METHODS

Animals and experimental design

A two period cross-over study was undertaken in six female

ponies of the Welsh Mountain breed, aged 2±14 years and

ranging in body weight from 220 to 342 kg (mean weights

278+15 kg and 276+14 kg in periods 1 and 2, respectively).

Animals were housed in individual loose boxes and fed hay plus

concentrate rations with free access to water. There was an

acclimatization period of 4 weeks before commencement of the

study. In period 1, three ponies received a bolus dose of

vedaprofen (1 mg/kg) as a sterile aqueous solution (50 mg/mL)

and three ponies received an equivalent volume of placebo

product (sterile saline) into the right jugular vein at time 0. In

period 2, carried out 28 days later, treatments were reversed.

Dose volume was 2 mL/100 kg.

Induction of inflammatory reaction

A mild inflammatory response was induced in the neck of each

pony (period 1: left; period 2: right) by insertion of five polyester

sponge strips (2562565 mm) soaked in sterile 1% carragee-

nan solution into subcutaneous pouches dissected under local

anaesthesia (2% lignocaine hydrochloride, Lignocaine and

Adrenaline Solution, Norbrook Laboratories Ltd, Newry, N.

Ireland) (Higgins & Lees, 1984) and these were removed serially

at predetermined times up to 8 h. Five further sponges soaked in

1% sterile carrageenan solution were then inserted.

Lesion swelling at the site of carrageenan sponge insertion was

quantified at predetermined times by measuring with vernier

callipers two perpendicular diameters and lesion depth. From

these measurements, assuming lesion shape to be that of half an

ellipsoid, approximate lesion volume was determined from the

formula, V=2/3 p r1.r2.r3, where V=volume and r1, r2 and

r3 are radii. Measurements were taken by an independent asses-

sor who was unaware both of the nature of the investigation and

the fact that animals received either drug or placebo treatments.

Collection of blood and exudate samples

Blood samples for the collection of plasma and serumwere taken at

predetermined times into 7 mL vacutainers. For plasma, tubes

contained lithium heparin as anticoagulant and samples were

placed on ice immediately after collection. For ex vivo serum TXB2generation, blood samples were allowed to clot for 60 min in a

water bath at 37 8C. Tubes were then placed on ice. Serum and

plasma were collected by centrifugation (25006g, 4 8C, 15 min)

and the supernatants stored at ±20 8C until analysis for vedaprofen

enantiomer concentrations (plasma) and TXB2 concentrations

(serum). Additional blood samples (5 mL) were collected in EDTA

tubes for determination of whole blood platelet count.

Polyester sponges containing acute inflammatory exudate

were removed serially at predetermined times up to 48 h. From

each sponge inflammatory exudate was collected as previously

described into tubes containing BW540C, a dual cyclo-oxyge-

nase 5-lipoxygenase inhibitor, to prevent artefactual in vitro

generation of eicosanoids (Higgins & Lees, 1984; Higgins et al.,

1984a). Following removal of a 0.1-mL aliquot, for measure-

ment of leucocyte numbers, samples were centrifuged

(25006 g, 4 8C, 10 min) to separate cells. The supernatants

were divided into aliquots prior to storage at ±20 8C until

analysed for TXB2, PGE2 and vedaprofen concentrations.

Analytical methods

Platelet count and eicosanoid assays

Blood platelet count was determined as described by Lees et al.

(1987a). Exudate white cell count was measured using a Coulter

counter as described by Lees et al. (1987a). The eicosanoids,

TXB2 in serum and exudate and PGE2 in exudate, were

measured using radioimmunoassays as previously described

(Higgins & Lees, 1984; Lees et al., 1987a).

Vedaprofen enantiomer analysis in plasma and exudate

Concentrations of vedaprofen enantiomers were determined by

high pressure liquid chromatography (HPLC). Solid phase

extraction was followed by enantioselective HPLC using a chiral

stationary phase. The conditions were as follows. Plasma

samples (1 mL) were diluted with 0.1 mL distilled water,

#1999 Blackwell Science Ltd, J. vet. Pharmacol. Therap. 22, 96±106

Vedaprofen in the horse 97

Paper 173 Disc

acidified with 2 mL 2 M acetic acid and extracted by solid phase

extraction. To a C18 Bond Elut cartridge the following were

applied successively: 2.5 mL methanol and 2.5 mL 2 M acetic

acid followed by 2.5 mL of the sample. The cartridge was then

washed with 5 mL 2 M acetic acid followed by 2.5 mL distilled

water. The cartridge was eluted with 2.5 mL methanol and the

eluate evaporated to dryness in a centrifugal evaporator. The

residue was dissolved in 2 mL of a mixture of 0.01 M NaH2PO4

pH=7.0: 2-propanol, 90: 10 v/v. The solution was vortexed

and ultrasonified for 2 min then centrifuged for 10 min at

14006 g. The supernatant was used for chromatography.

Chromatographic conditions were as follows:

Analytical column: Bakerbound Chiral-AGP column

(10064.0 mm).

Mobile phase: 0.01 M NaH2PO4 pH=7.0/2-propanol 90/10 v/v.

Flow rate: 0.9 mL/min.

Injection volume: 50 mL.Detection: Fluorescence; Excitation 210 nm, Emission 325 nm.

Column-heater: 30 8C.Concentrations of vedaprofen enantiomers in plasma and

exudate were determined by measurement of peak areas and

comparison with a calibration curve prepared using vedaprofen

racemic mixture. The limits of detection were 11.6 and 9.2 ng/mL

for R(±) and S(+) vedaprofen, respectively. The limit of

quantification was 19.5 ng/mL (both enantiomers). Calibration

curves for both enantiomers were linear over the range 19.5±

1250 ng/mL. Mean accuracies were 99.2% (R(±)) and 99.9%

(S(+)) and recoveries from plasma compared to the mobile phase

were 95.9 and 97.6% for R(±) and S(+) vedaprofen, respectively.

Vedaprofen analysis in protein free plasma/exudate

For in vivo determination of vedaprofen binding to plasma and

exudate protein, protein free plasma/exudate was prepared by

ultrafiltration using a micro partition system (MPS 1 system,

Amicon, Dronten, The Netherlands). Plasma and exudate

samples were equilibrated at 37 8C for 30 min. Assembled

reservoirs of the micro partition system were filled with plasma

and then centrifuged for 30 min at 10006 g at room

temperature (20 8C). Protein free plasma (i.e. ultrafiltrate)

samples were stored frozen (±20+3 8C) until analysis.Vedaprofen as racemate was analysed in the ultrafiltrate

samples by reversed phase HPLC. Briefly, plasma/exudate

ultrafiltrate was acidified by adding an equal volume of 1.2 M

HCl, mixed thoroughly and left for 1 h at room temperature

(20 8C). The sample was extracted by a tenfold volume of ether.

The organic phase was separated and evaporated to dryness and

the residue dissolved in 250 mL 0.1 M NaOH and subjected to

HPLC analysis. The HPLC system was as follows: column

Lichrosorb C18 length 10 cm, eluent 65% acetonitrile: 35%

water in 1% acetic acid, flow 0.6 mL/min, injection volume 10

mL, UV detection at 288 nm.

In the in vitro protein binding study, plasma from six untreated

horses (three mares and three geldings) was spiked with 25.0 mg/mL vedaprofen as racemate. Protein free plasma was prepared as

described for plasma/exudate in the in vivo study. Standards of

pure enantiomers were prepared in ultrafiltrate, obtained from

plasma of untreated horses. Standards contained between 19.5

and 781 ng/mL vedaprofen ultrafiltrate. The limits of detection of

the R(±) and S(+) enantiomers were 3 and 6 ng/mL, respectively.

The lowest standard contained & 20 ng/mL vedaprofen

equivalent to & 10 ng/mL of each of the enantiomers.

Analysis of data

Plasma and exudate concentration±time relationships were

evaluated using standard pharmacokinetic methods. Plasma

pharmacokinetic parameters were estimated by fitting the

concentration time data to an appropriate model by means of an

ELSFIT computer program version 3.1. Area under the curve

(AUC) and area under the first moment curve (AUMC) were

calculated using the linear trapezoidal rule. Clearance (Cl) was

derived from Dose/AUC and the mean residence time (MRT) from

AUMC/AUC. Exudate pharmacokinetic parameters were estimated

by the curve stripping procedure according to Wagner (1975).

Pharmacokinetic-pharmacodynamic modelling for inhibition of

serum TXB2 and exudate PGE2 was undertaken by the method of

Sheiner et al. (1979). Serum TXB2 and exudate PGE2 data were

fitted to the sigmoid Emax model by linear regression analysis of

the double-reciprocal curves, assuming that the Hill coefficient is

one and does not include an equilibration time. Values reported are

mean+SEM and the significance of differences of means between

drug and placebo treated animals was assessed by Student's t-test

for paired values. The level of significance was 0.05.

RESULTS

Pharmacokinetics

The plasma pharmacokinetics of vedaprofen enantiomers was

described by a 2 compartment open model in all six ponies. The

plasma disposition of S(+) vedaprofen was characterised by

initial rapid decline from 3112 ng/mL at 5 min to 244 ng/mL at

1 h and a further decline to 27 ng/mL at 3 h. Concentrations of

the R(±) enantiomer at the same times were 6892, 2468 and

555 ng/mL, respectively. By 10 h the concentration of R(±) had

fallen to 40 ng/mL (Table 1).

The predominance of the R(±) enantiomer in plasma following

intravenous injection of rac-vedaprofen was established rapidly.

Five minutes after administration the mean R : S plasma

concentration ratio was 69: 31 and by 2 h this had increased

to 95 : 5 (Table 1). R(±) vedaprofen plasma concentrations

exceeded the limit of quantification for 10 h, but S(+)

vedaprofen was measurable in plasma for only 3 h. Enantios-

electivity of vedaprofen pharmacokinetics was also reflected in

differences in AUC values. Percentage AUC values were 83 and

17 for R(±) and S(+) enantiomers, respectively (Table 2).

The predominance of R(±) vedaprofen in plasma was

attributable to both distribution and elimination phase differ-

ences. The distribution half-lives of R(±) and S(+) vedaprofen

were 0.53 and 0.20 h, respectively (Table 2). Volume of the

central compartment was almost twice as great for S(+)

98 P. Lees et al.


Paper 173 Disc

vedaprofen and volume of distribution of the S(+) enantiomer

was more than twice that of R(±) vedaprofen (Table 2). The

greater tendency of S(+) vedaprofen to penetrate into the

peripheral compartment is indicated by the higher K12 value for

the S(+) enantiomer. However, K21 values were similar for R(±)

and S(+) vedaprofen.

Elimination half-life was three times longer for R(±) vedapro-

fen, the mean values being 2.22 and 0.76 h for R(±) and S(+)

vedaprofen, respectively. The half-life and volume of distribution

differences between vedaprofen enantiomers resulted in marked

differences in plasma clearance. Mean values were 0.069 L/h/kg

(R(±)) and 0.396 L/h/kg (S(+) vedaprofen). The elimination

rate constant (K10) was 3±6 times greater for S(+) than for

R(±) vedaprofen.

R(±) vedaprofen also predominated in inflammatory exudate,

although both enantiomers readily accumulated in and were

more slowly cleared from exudate than from plasma. Thus, R(±)

enantiomer concentrations in exudate were quantifiable for

24 h, whilst S(+) vedaprofen exceeded the limit of quantification

for 12 h (Table 1). Mean maximum concentration (Cmax) for R(±)

vedaprofen was twice and AUC more than twice the correspond-

ing values for the S(+)-antipode (Table 3). However, concentra-

tion differences between enantiomers in exudate was not as high

as those in plasma. Thus, at 1 h R: S concentration ratios were

91 : 9 for plasma and 66 : 34 for exudate. Corresponding values



Table 1. Plasma and exudate concentrations of vedaprofen enantiomers following i.v. injection of 1 mg/kg rac-vedaprofen

Plasma concentration Exudate concentrations

ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

(ng/mL) (%) (ng/mL) (%)

ÐÐÐÐÐÐÐÐÐÐÐÐÐÐ ÐÐÐÐÐÐÐÐÐÐÐÐÐÐ ÐÐÐÐÐÐÐÐÐÐÐÐÐÐ ÐÐÐÐÐÐÐÐÐÐÐÐÐ

R (±) S (+) R (±) S (+) R (±) S (+) R (±) S (+)

Time ÐÐÐÐÐÐÐ ÐÐÐÐÐÐ ÐÐÐÐÐÐ ÐÐÐÐÐÐ ÐÐÐÐÐÐ ÐÐÐÐÐÐ ÐÐÐÐÐÐ ÐÐÐÐÐÐ

(h) mean SEM mean SEM mean SEM mean SEM mean SEM mean SEM mean SEM mean SEM

0.08 6892 403 3112 229 69 1 31 1

0.17 6451 715 2278 252 74 1 26 1

0.33 3976 334 946 108 81 1 19 1

0.50 4114 302 919 160 82 2 18 2

0.75 2953 250 377 57 89 1 11 1

1.00 2468 296 244 45 91 1 9 1 2325 763 1435 581 66 5 34 5

1.50 1516 154 128 33 92 2 8 2

2.00 1034 166 59 12 95 1 5 1 2393 705 1115 387 71 5 29 5

3.00 555 73 27 3 96 0 4 0

4.00 229 37 5 LOQ 1098 122 480 169 72 5 28 5

6.00 75 17 5 LOQ 558 103 195 91 78 5 22 5

8.00 35 7 5 LOQ 186 40 40 15 83 3 17 3

10.0 40 15 5 LOQ 133 27 27 5 83 1 17 1

12.0 5 LOQ 5 LOQ 85 31 23 1 76 12 24 12

15.0 5 LOQ 5 LOQ 36 6 5 LOQ

24.0 5 LOQ 5 LOQ 37 6 5 LOQ

36.0 5 LOQ 5 LOQ 5 LOQ 5 LOQ

48.0 5 LOQ 5 LOQ 5 LOQ 5 LOQ

Values are mean+ SEM (n=5). LOQ=Limit of quantitation (19.5 ng/mL).

Table 2. Pharmacokinetic parameters of vedaprofen enantiomers

following i.v. injection of 1 mg/kg rac-vedaprofen

Parameter R (±) Enantiomer S (+) Enantiomer

A (ng/mL) 4421+1027 3499+197

t1/2a (h) 0.53+0.15 0.20+0.04

B (ng/mL) 2381+1300 495+163

t1/2b (h) 2.22+0.59 0.76+0.16

Vc (L/kg) 0.077+0.009 0.132+0.011

Vd (L/kg) 0.225+0.068 0.502+0.101

C1 (L/h/kg) 0.069+0.007 0.396+0.079

k12 (h71) 0.35+0.21 0.83+0.24

k21 (h71) 1.63+1.02 1.42+0.27

k10 (h71) 0.87+0.05 3.17+0.35

MRT (h) 1.40+0.06 0.67+0.20

AUC (ng.h/mL) 7524+613 1639+516

AUC (%) 83+4 17+4

AUMC (ng.h2/mL) 10589+1128 1499+949

Values are mean+ SEM (n=5).

Table 3. Pharmacokinetic parameters of vedaprofen enantiomers in

exudate following i.v. injection of 1 mg/kg rac-vedaprofen

Parameter R (±) Enantiomer S (+) Enantiomer

Cmax (ng/mL) 2950+755 1534+568

tmax (h) 2.0+0.7 1.3+0.3

MRT (h) 3.67+0.49 3.07+0.38

AUC (ng.h/mL) 9755+1632 4400+1428

AUC (%) 72+5 28+5

AUMC (ng.h2/mL) 34237+5410 12005+3188

Exudate: plasma AUC ratio 1.3+0.2 3.8+1.1

Exudate: plasma MRT ratio 2.6+0.4 6.7+1.0


Paper 173 Disc

at 3 h were 96 : 4 (plasma) and 72 : 28 (exudate) and by 10 h the

ratio for exudate had increased to 83 : 17. The relatively greater

penetration of S(+) vedaprofen into inflammatory exudate may

be expected from its higher volume of distribution compared to

the R(±) antipode (Table 2) and is further reflected in the mean

values of exudate: plasma AUC ratio (1.3 for R(±) and 3.8 for

S(+) vedaprofen) and exudate: plasma MRT ratio (2.6 for R(±)

and 6.7 for S(+) vedaprofen).

The in vivo binding of vedaprofen (total concentration) to

plasma and exudate protein was investigated on samples

collected in period 1 of the study. At 5 min and 1 h the degree

of binding was very high; mean values for percentage unbound

vedaprofen were 0.344 and 0.523, respectively (Table 4).

Binding to exudate protein was also high; at 6 h the percentage

of total drug unbound was 0.797.

The binding of vedaprofen enantiomers to plasma protein was

investigated in vitro. Plasma collected from six horses was spiked

with 25 mg/mL rac-vedaprofen. Mean percentage unbound

fractions were 0.10 and 0.35 for R(±) and S(+) vedaprofen,

respectively (Table 5).

Pharmacodynamics

Lesion swelling was greatest and relatively constant between 10

and 36 h in both groups. However, at all measuring times

between 0.5 and 48 h mean lesion volume was reduced by rac-

vedaprofen (Fig. 2). Differences between the groups were small

initially (0.5, 1 and 2 h). At most measuring times between 4

and 48 h, vedaprofen reduced swelling by about one half

compared to placebo.

100 P. Lees et al.


Concentration (mg/mL)

ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ

Pony Time (h) Total Unbound Percentage unbound

Plasma

A 0.08 9.784 0.031 0.316

B 0.08 10.399 0.046 0.442

C 0.08 8.396 0.023 0.274

Mean+ SEM 9.52+0.59 0.033+0.007 0.344+0.050

A 1 3.027 0.015 0.496

B 1 6.298 0.026 0.413

C 1 2.119 0.014 0.661

Mean+ SEM 3.815+1.269 0.018+0.004 0.523+0.073

A 4 0.301 5 DL ±

B 4 0.210 5 DL ±

C 4 0.298 5 DL ±

Mean+ SEM 0.270+0.030

Exudate

B 6 1.756 0.014 0.797

B 8 0.589 5 DL ±

B 10 0.189 5 DL ±

B 12 0.176 5 DL ±

DL=Detection limit.

Table 4. In vivo binding of vedaprofen

to plasma and exudate protein

following i.v. injection of 1 mg/kg rac-

vedaprofen

Table 5. In vitro protein binding of

vedaprofen following spiking of plasma

with the racemate at a concentration of

25 mg/mL

Unbound Unbound Unbound

concentration fraction (±): (+)

(ng/mL) (%) ratio (%)

ÐÐÐÐÐÐÐÐÐÐÐÐÐÐ ÐÐÐÐÐÐÐÐÐÐÐÐ ÐÐÐÐÐÐÐÐ

Pony R (±) S (+) Total R (±) S (+) Total R (±) S (+)

1 14 47 61 0.11 0.38 0.24 23 77

2 21 56 77 0.17 0.45 0.31 27 73

3 16 47 63 0.13 0.38 0.25 25 75

4 5 31 36 0.04 0.25 0.14 14 86

5 5 LOD 43 43 5 LOD 0.34 0.17

6 4 35 39 0.03 0.28 0.16 10 90

Mean 11 43 54 0.10 0.35 0.21 20 80

SEM 3 4 6 0.03 0.03 0.03 3 3

Horses 1, 2 and 3 were mares; 3, 4 and 5 were geldings. LOD (limit of detection) of R (±) enantiomer=3 ng/mL

ultrafiltrate LOD of S (+) enantiomer=6 ng/mL ultrafiltrate.

Paper 173 Disc

Leucocyte infiltration into exudate was low at all sampling

times up to 8 h, was higher between 10 and 48 h and maximal

at 36 h in placebo treated animals (Fig. 3). Partial inhibition

(ranging from 63 to 78%) of leucocyte infiltration occurred in

rac-vedaprofen treated ponies, and this effect was statistically

significant between 10 and 24 h (P 5 0.05).

Circulating platelet numbers did not change with time and

there were no significant differences between placebo and

vedaprofen treatments (Fig. 4). Serum TXB2 concentration was

relatively constant in placebo-treated ponies. Rac-vedaprofen

inhibited serum TXB2 synthesis in a time-dependent manner

(Fig. 5); differences from placebo treatment were statistically

significant at all sampling times between 1 and 48 h. Inhibition

was almost complete initially (1 and 2 h) and still apparent at a

level of & 50% at later sampling times (24±48 h). In contrast,

inhibition of exudate TXB2 synthesis was both less marked and

more transient (Fig. 6). Thus, significant inhibition occurred for

6 h only after drug administration.

The concentration of PGE2 in inflammatory exudate of placebo

treated horses was low at both early (1±2 h) and later (24±48 h)

sampling times, with peak concentrations occurring at 4±8 h

(Fig. 7). The magnitude and time course of inhibition of PGE2synthesis by vedaprofen were similar to those described for

exudate TXB2; a moderate degree of inhibition was obtained up

to 8 h (87% at 2 h, 70% at 4 h, 54% at 6 h and 25% at 8 h). The

smaller degree of inhibition occurring at most subsequent times

was not statistically significant.

PK-PD modelling of data for serum TXB2 and exudate PGE2inhibition indicated Emax values of 84% and 95%, respectively

(Table 6). However, the potency of rac-vedaprofen for inhibition



Fig. 2. Lesion volumes in placebo and rac-

vedaprofen (1 mg/kg) treated horses. Values are

mean+ SEM (n=6).

Fig. 3. Exudate leucocyte count in placebo and

rac-vedaprofen (1 mg/kg) treated horses. Values

are mean+ SEM (n=6).

Paper 173 Disc

of serum TXB2 and exudate PGE2 was markedly different;

respective EC50 values were 9.44 and 630 ng/mL (Table 6).

DISCUSSION

The pharmacokinetic and pharmacodynamic properties of

vedaprofen in this acute nonimmune inflammation model in

the horse were comparable to those found for other 2-

arylpropionates, which have recently been licensed for use in

this species. For example, the racemates of vedaprofen (1 mg/kg),

ketoprofen (2.2 mg/kg) and carprofen (0.7 mg/kg) all demon-

strate enantioselective pharmacokinetics and all produce partial

inhibition of COX, the enzyme that catalyses the conversion of

arachidonic acid to eicosanoids associated with blood clotting

(TXA2) or synthesised at sites of acute inflammation to produce

hyperalgesia, vasodilation and oedema (PGE2). However, there

are also significant differences as well as similarities between 2-

arylpropionate pharmacodynamic and pharmacokinetic proper-

ties in the horse. Thus, of these three drugs, carprofen produced

the smallest degree of inhibition at these dosages. Moreover,

vedaprofen and ketoprofen are similar in that both enantiomers

of both drugs possess low to moderate volumes of distribution

(0.225±0.502 L/kg for R(±) and S(+) vedaprofen and 0.472 and

0.491 L/kg for R(±) and S(+) ketoprofen, respectively) (this

paper and Landoni & Lees, 1995). These volumes of distribution

are not high but, given that 2-arylpropionates are highly bound

to plasma protein, they represent good tissue penetration

(Landoni & Lees, 1995, 1996a). In comparison, other NSAIDs

which are also highly bound to plasma protein, such as flunixin

102 P. Lees et al.


Fig. 4. Blood platelet count in placebo and rac-

vedaprofen treated horses. Values are

mean+ SEM (n=6).

Fig. 5. Ex vivo serum TXB2 generation in

placebo and rac-vedaprofen treated horses.


Paper 173 Disc

and phenylbutazone, have somewhat lower (less than 0.2 L/kg)

volumes of distribution in the horse (Higgins et al., 1986; Lees et

al., 1986, 1987a, b).

Both enantiomers of ketoprofen and vedaprofen are also

similar in possessing short elimination half-lives (2.22 and 0.76

h for R(±) and S(+) vedaprofen and 1.09 and 1.51 h for R(±)and

S(+) ketoprofen, respectively) (Landoni & Lees, 1996a).

Jaussaud et al. (1993) reported even shorter half-lives for

ketoprofen enantiomers in the horse (18±31 min for R(±)

ketoprofen and 22±29 min for the S(+) enantiomer). Carprofen

enantiomers are eliminated much more slowly; t�b-values are

24.5 and 8.0 h at a dosage of 0.7 mg/kg and 22.2 and 11.3 h at

a dosage of 4.0 mg/kg for R(±) and S(+) carprofen, respectively

(Shojaee AliAbadi, Landoni and Lees, unpublished data).



Fig. 7. Exudate PGE2 synthesis in placebo and

rac-vedaprofen treated horses. Values are

mean+ SEM (n=6).

Fig. 6. Exudate TXB2 synthesis in placebo and

rac-vedaprofen treated horses. Values are

mean+ SEM (n=6).

Table 6. Pharmacodynamic parameters for inhibition of serum TXB2and exudate PGE2 by vedaprofen

Serum TXB2 inhibition Exudate PGE2 inhibition

ÐÐÐÐÐÐÐÐÐÐÐ ÐÐÐÐÐÐÐÐÐÐÐÐ

Pony Emax (%) EC50 (ng/mL) Emax (%) EC50 (ng/mL)

A 87.5 6.83 166.7 995

B 88.3 4.78 81.6 924

C 81.7 29.30 41.1 194

E 86.4 4.50 72.3 482

F 75.4 1.77 111.0 556

Mean+ SEM 83.9+2.4 9.44+5.00 94.5+21.2 630+148

Paper 173 Disc

The S(+) enantiomer of ketoprofen predominates following rac-

ketoprofen administration and this is due to unidirectional chiral

inversion of R(±) to S(+) ketoprofen (Landoni & Lees, 1996a, b).

On the other hand, for carprofen, the R(±) enantiomer predomi-

nates in plasma and other biological fluids (Lees et al., 1991a,

Shojaee AliAbadi et al. unpublished data) and there is no chiral

inversion of this drug in the horse (Shojaee AliAbadi et al.

unpublished data). After rac-carprofen administration to the horse,

the plasma concentration AUC ratio, R : S, was 82 : 18. The

corresponding R : S ratio for ketoprofen was 42 : 58 and in this

study, the ratio for vedaprofen was 83 : 17, which is almost

identical to the carprofen ratio. When chiral inversion of 2-

arylpropionates does occur (and it varies between both drugs and

species), it is almost invariably unidirectional, R(±) to S(+). Hence,

the predominance of R(±) vedaprofen revealed in this equine study

will almost certainly be due, not to S(+) to R(±) inversion, but to

the greater volume of distribution and hence greater tissue

penetration together with a shorter elimination half-life of S(+)

vedaprofen. These differences accounted for the 5.7 fold greater

plasma clearance of S(+) compared to R(±) vedaprofen.

Previous studies in this laboratory have shown that, in the

horse, 2-arylpropionate (ketoprofen and carprofen) and other

NSAIDs (phenylbutazone, flunixin and meloxicam) penetrate

readily into and are slowly cleared from inflammatory exudate

(Higgins et al., 1984b, 1986, 1987; Lees & Higgins, 1984; Lees

et al., 1986, 1991a, b, 1994a; Landoni & Lees, 1995, 1996a).

Penetration has been shown to be particularly high for both

S(+) and R(±) ketoprofen enantiomers, with exudate: plasma

AUC ratios of the order of 15 : 1 (Landoni & Lees, 1995, 1996a).

This had been ascribed, at least in part, to the high degree of

binding to plasma protein of NSAIDs and the leakage of protein

(with bound drug) into oedema fluid as a direct consequence of

altered microvascular permeability at acute inflammatory sites.

However, other factors may be involved, as the extent of

penetration varies between drugs, but all are highly bound to

plasma protein.

The present study confirms that both vedaprofen enantiomers

also penetrated readily into and were slowly cleared from

inflammatory exudate in the horse. Thus, for both vedaprofen

enantiomers mean residence times and AUC values were greater

for exudate than plasma (Tables 2 and 3). In exudate,

concentrations of R(±) vedaprofen were greater than those of

the entantiomer S(+), which is not surprising in view of the

much higher plasma concentrations of the former. However,

differences were not as large as in plasma. This resulted in a

degree of enantioselectivity in favour of S(+) vedaprofen for

accumulation in exudate, reflected in the higher exudate: plasma

AUC and MRT ratios.

The explanation for the latter finding is not known, but it is

unlikely to reflect differences in physico-chemical properties,

such as lipid solubility, as enantiomeric pairs almost invariably

possess similar physico-chemical properties. On the other hand,

as the body is a highly chiral environment, enantiomeric pairs

commonly differ in those pharmacokinetic and pharmacody-

namic properties which reflect interactions with chiral molecules

in vivo. For example, enantiomers often differ in the degree of

binding to plasma protein. In this study, total drug binding to

plasma and exudate protein in vivo was shown to be very high

(in excess of 99%). In vitro studies confirmed the high degree of

binding to plasma protein and demonstrated that, at a spiking

concentration of 25 mg/mL, the unbound fractions were 0.10

and 0.35 mg/mL for R(±) and S(+) vedaprofen, respectively. This

finding may explain the higher volume of distribution, higher

volume of the central compartment and greater relative

penetration into inflammatory exudate of S(+) vedaprofen.

It has been widely assumed that inhibition of COX is the

primary means by which NSAIDs exert both their therapeutic

and toxic side-effects (Higgs et al., 1981), since the elucidation of

this mechanism by Vane (1971) and Smith & Willis (1971).

Most NSAIDs are indeed potent inhibitors of COX and a number

(including phenylbutazone, meloxicam, flunixin, tolfenamic acid

and ketoprofen) have been shown to produce marked and even

complete inhibition of prostanoid synthesis at clinical dosages in

several species of veterinary importance (Higgins et al., 1984b,

1987; Lees & Higgins, 1984; McKellar et al., 1989, 1994a, b;

Taylor et al., 1991, 1994; Landoni et al., 1995; Landoni & Lees,

1995, 1996b). However, not all NSAIDs are potent COX

inhibitors, and several COX independent effects have been

reported. These may be nonenantioselective (Twomey & Dale,

1992; Villaneuva et al., 1993).

In the light of the above findings, the present data with

vedaprofen are of interest for several reasons. Administration

of the racemate produced prolonged inhibition of ex vivo serum

TXB2 synthesis, in spite of the relatively rapid clearance of both

enantiomers from plasma. This is somewhat surprising as

TXB2 is produced by platelets when blood clots and inhibition

is therefore likely to be dependent on circulating drug

concentrations. Moreover, many studies have demonstrated

that it is the S(+) enantiomer of 2-arylpropionates which is

the eutomer for COX inhibition, with a potency orders of

magnitude greater than the R(±) antipode (Hutt & Caldwell,

1983; Caldwell et al., 1988; Evans, 1992; Suesa et al., 1993).

In the present study S(+) vedaprofen concentration had

decreased to 27 ng/mL 3 h after dosing, whilst inhibition of

serum TXB2 persisted for much longer. This might be due to

the high potency of S(+) as an inhibitor of platelet COX, to an

inhibitory action of R(±) vedaprofen with the high plasma

concentration achieved, to concentration of one or both

enantiomers within platelets, to hysteresis in the action of

the drug or to a combination of these factors.

In contrast, the inhibition of exudate PGE2 synthesis following

rac-vedaprofen administration was moderate and evanescent.

This is somewhat surprising, as mean exudate concentrations of

S(+) vedaprofen were 5.9 and 18.9 times greater than

corresponding plasma concentrations 1 and 2 h after dosing,

respectively. Calculation of the EC50 values for inhibition of

serum TXB2 and exudate PGE2 revealed a 66 fold difference in

potency in favour of serum TXB2. For other NSAIDs studied in

this laboratory (ketoprofen, tolfenamic acid and flunixin)

potency differences have also been demonstrated for inhibition

of synthesis of PGE2 and TXB2 but the differences have been

smaller, usually no more than 3-fold (Landoni et al., 1995,

104 P. Lees et al.


Paper 173 Disc

1996; Landoni & Lees, 1995, 1996a). However, it should be

noted that in the latter studies a tissue cage model of

inflammation was used and direct comparison with the sponge

model used in this investigation may not be appropriate. In vitro

studies have yielded markedly different results for inhibition of

COX isoenzymes with differing cell types and experimental

conditions. For in vivo studies it is similarly possible that EC50values will be model dependent. Drug accumulation rate and

persistence may differ in the tissue cage and sponge models and

the granulation tissue inside cages may be more or less reactive

than the tissue stimulated in the sponge model.

It is now recognised that there are two isoforms of COX. COX-1

is a constitutive enzyme, present in most cell types including

platelets, which is believed to subserve a range of physiological

functions such as gastroprotection, renoprotection and, in the

case of blood platelets, clotting (TXA2 is a potent pro-aggregatory

agent). COX-2, on the other hand, is an inducible enzyme formed

by leucocytes and tissue cells in response to mitogens,

lipopolysaccharide and inflammatory stimuli. COX-2 is capable

of generating large quantities of PGE2 but peak production is

delayed for several hours as it is dependent on protein synthesis.

It has been proposed that inhibition of COX-1 may be responsible

for most of the side-effects of NSAIDs, such as gastric irritation,

whilst COX-2 inhibition is believed to underlie the therapeutic

analgesic, anti-inflammatory and antipyretic actions (Vane &

Botting, 1998; Bakhle & Botting, 1996). COX-2/COX-1 inhibi-

tory activities of NSAIDs are generally determined in in vitro

systems using, for example, stimulated macrophages (COX-2)

and aortic endothelial cells (COX-1).

The finding in this study that EC50 for inhibition of COX-1

(indicated by serum TXB2) is much lower than the EC50 for

inhibition of COX-2 (indicated by exudate PGE2) implies a degree

of vedaprofen selectivity in favour of COX-1, located in blood

platelets and reflecting most likely the antithrombotic activity of

this compound. Although blood platelet cyclo-oxygenase is

considered under the current hypothesis as a COX-1 enzyme,

because it is a constitutive enzyme, it is suggested that platelets

should be considered as inflammatory cells as they participate in

inflammation particularly in vascular inflammation, through the

release and expression of regulatory molecules (Mannaioni et al.,

1997). Much current research is directed towards the evaluation

of highly specific COX-2 inhibitors, on the assumption that they

may have wider safety margins than the currently available

nonselective COX inhibitors. However, at the present time it is

not clear whether differences in EC50 values for COX-1 and COX-

2 established in vitro are associated with NSAID toxicity: efficacy

ratios in vivo. For example, whether compounds with partial

selectivity for COX-2, such as meloxicam and nimesulide, have

wider safety margins in clinical use than other NSAIDs with no

selectivity is uncertain. Moreover, as noted above, it is now

recognised that the actions of NSAIDs are complex and both

therapeutic and toxic actions may be due, in part, to COX

independent mechanisms. It cannot be assumed that S(+)

enantiomers of 2-arylpropionates will be the eutomers for such

actions. Indeed, the reports of Villaneuva et al. (1993), Brune et

al. (1992) and McCormack & Brune (1991) indicate equal

potencies of R(±) and S(+) enantiomers for some biological

actions of this class of NSAIDs. In this study, rac-vedaprofen not

only produced significant inhibition of inflammatory swelling

but also partially inhibited the migration of leucocytes into

inflammatory exudate (other NSAIDs studied in our laboratory

have generally failed to affect leucocyte migration into inflam-

matory exudate). Whether either of these actions is due to a non-

COX mechanism and whether the effects are attributable to one

or both enantiomers of vedaprofen remains unclear.

ACKNOWLEDGMENTS

We are grateful to Mrs R Foot, Miss R Hooke and Ms P Marks

who provided skilled technical assistance.

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