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Bioavailability of racemic ketoprofen in healthy horses following rectal administration
Research in Veterinary Science 1999, 67, 201–202 Article No. rvsc.1999.0303, available online at http://idealibrary.com on
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Bioavailability of racemic ketoprofen in healthy horses following rectal administration S. CORVELEYN*, D. HENRIST*, J.P. REMON*, G. VAN DER WEKEN†, W. BAEYENS†, J. HAUSTRAETE†, H.Y. ABOUL-ENEIN‡, B. SUSTRONCK§, P. DEPREZ§
*Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of Gent, Harelbekestraat 72, 9000 Gent, Belgium, †Laboratory of Drug Analysis, Faculty of Pharmaceutical Sciences, University of Gent, Harelbekestraat 72, 9000 Gent, Belgium, ‡Biological and Medical Research Department, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi-Arabia, §Department of Internal Diseases of Large Animals, Faculty of Veterinary Medicine, University of Gent, Salisburrylaan 133, 9820 Merelbeke, Belgium SUMMARY Ketoprofen (KTP) is a chiral non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class, approved by the FDA for the allevation of pain associated with musculoskeletal disorders in horses. The present study was designed to examine the bioavailability of ketoprofen enantiomers after rectal administration of the racemate to healthy horses. One gram of racemic ketoprofen was injected intravenously and administered rectally as a fat based suppository in a cross-over design study (n = 4). Blood samples were analysed for KTP enantiomers using HPLC. After IV administration, the S(+) enantiomer concentrations in plasma were higher than the R(–) enantiomer concentrations and the AUC0–12 h for the S(+) enantiomer was significantly higher than for the R(–) enantiomer. Following rectal administration Cmax and AUC0–12 h were significantly higher for the S(+) than for the R(–) enantiomer. Bioavailability after rectal administration was low. Since there was no significant difference in bioavailability between the two enantiomers, it is assumed that no pre-systemic inversion from R(–) to S(+) occurred after rectal administration of racemic KTP to horses. © 1999 Harcourt Publishers Limited
KETOPROFEN (KTP) is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class. It is a chiral molecule, existing as two enantiomers, S(+) and R(–) KTP. The recommended maximal dose for horses is 2·2 mg kg–1 body weight daily for a maximum of 5 days. The clinical application of rectal drug administration in horses has received little attention in the past. The lack of data on rectal absorption of drugs in horses, the lack of patient cooperation and the voluminous faecal production of herbivores such as the horse had a negative influence on the development of drug products for rectal administration (King 1994). However, there are indications for using this route of administration such as when the oral administration of medication is difficult due to non-compliance of patient or when gastrointestinal motility is severely impaired. In addition the oral route can not be used in some patients due to oral or oesophageal injuries or ulceration and in convulsing neonates rectal administration is easier than parenteral or oral administration (King 1994). In a previous study (Corveleyn et al 1996) the rectal bioavailability of ketoprofen in healthy horses was evaluated using two different suppository bases and one liquid suspension. It was reported that the absolute bioavailability of KTP in horses after rectal administration was relatively low (24·5 to 31·3 per cent) for the different formulations, with a large interindividual variability. This was also reported for rectally administered cisapride (Steel et al 1999). A number of studies have looked at the enantioselective pharmacokinetics of racemic KTP in man (Sallustio et al 1988) and various animal species including rats (Iwakawa et al 1991), mice (Jamali et al 1997), calves (Landoni and Lees 1995a) and horses (Landoni and
Corresponding author: J.P. Remon. Tel: ++32 9 264 80 54 Fax: ++32 9 222 82 36 E-mail: [email protected] 0034-5288/99/050201 + 02 $18.00/0
Lees 1995b). It was the objective of this study to examine the bioavailability of ketoprofen enantiomers after rectal administration of the racemate to horses. Four healthy mares with ages ranging from 6 to 12 years and weighing 415 to 540 kg were used in this study. The horses were fed 2 kg concentrate a day and had free access to hay and straw. Water was available ad libitum. An IV solution containing 10 per cent (w/v) racemic ketoprofen (Ketofen®, Rhone Mérieux, Lyon, France) and a suppository formulation containing 1 g of micronised racemic ketoprofen (Sigma Chemical Co, St. Louis, USA) in a hard fatty base (Witepsol H15, Hüls AG, Witten, Germany) were administered in a cross-over design study. A time interval of at least 1 week was allowed to elapse between each administration. The animals were fitted with an IV catheter at the beginning of the experiment. Blood samples (5 ml) were taken 5 minutes before and at predetermined time intervals after IV and rectal administration. Blood samples were collected in vacuum tubes (Venoject®, Kimble-Terumo, Elkton, MA, USA) containing heparin as an anticoagulant. Plasma was separated by centrifugation at 2000 g for 2 minutes and stored at –20°C until analysed. In order to analyse the KTP enantiomers in horse plasma a new HPLC method based on the application of an alkyl-diol-silica precolumn was developed and validated (Baeyens et al unpublished data). All reagents and instrumentation were from Merck (Darmstadt, Germany). The plasma samples, buffered with phosphate buffer (pH 7·0) were brought or to the pre-column (C 18 alkyl-diol-silica (ADS), 25 µm, 25 × 4 mm ID) by means of a six-port valve using a 0·1 M phosphate buffer, pH 7·0. After washing with the buffer for at least 11 minutes, the ADS-column was backflushed (flow rate 0·6 mL min–1) with the mobile phase (0·01 M phosphate buffer – 6 per cent (v/v) 2-propanol – 5 mM octanoic acid at pH 5·5), thus transporting the analytes over a chiral human serum albumin (HSA) 100 × 4·0 mm column (Advanced Separation Technologies Inc., © 1999 Harcourt Publishers Limited
202 S. Corveleyn, D. Henrist, J.P. Remon, G. Van der Weken, W. Baeyens, J. Haustraete, H.Y. Aboul-Enein, B. Sustronck, P. Deprez
TABLE 1: Bioavailability of S(+) KTP and R(–) KTP in horse plasma after a single IV dose and a rectal administration of 1 g rac-KTP (N=4). Mean (S.D.) Parameter
1. IV dose AUC0–12 h (µg.h/ml) 2. Rectal administration AUC0–12 h (µg.h/ml) Cmax (µ g/ml) Tmax (h) F (%)
S(+)KTP
R(–)KTP
6·7a (1·45)
4·6 (1·07)
1·8a (0·52) 1·05a (0·336) 1 (0·0) 28 (12·4)
1·2 (0·31) 0·78 (0·253) 0·9 (0·25) 28 (12·3)
a Significantly higher than R(–) enantiomer (Student’s t-test for paired data, P < 0·05).
1.4 1.2 Concentration (ug ml–1)
New Jersey, USA) provided with a guard column 10 × 3·0 mm (kept at 30°C) where the separation of the KTP enantiomers (resolution 1·4) was achieved with UV detection at 260 nm. The limit of detection in plasma was 7 ng ml–1 for S(+) and 10 ng ml–1 for R(–) ketoprofen. Intra-assay variability (N=10) was between 1·4 and 2·8 per cent. Linearity and recovery for S(+) and R(–) KTP were in the ranges 0·9988 to 0·9999 and 92·1 to 102·0 per cent, respectively. The individual concentration-time profiles were analysed by MW/PHARM version 3·0 (Mediware 1987–1991, Utrecht, The Netherlands). The IV data fitted a two-compartment model (r2=0·99). The AUC0–12 h were calculated using the logarithmic and linear trapezoidal rules. The maximum plasma ketoprofen concentration (Cmax) and the time to reach the maximum plasma concentration (tmax) following rectal administration were determined from the individual plasma concentration-time profiles. F is a measure for the amount of drug absorbed, expressed as a percentage of the dose. All results are presented as mean ± SD. Data were analysed statistically by use of the Student’s t-test for paired data; the level of significance was P<0·05. The drug plasma concentration-time profile following IV dosing was described by a two-compartment open model. After IV administration, the R(–) enantiomer concentrations were lower compared to the S(+) enantiomer concentrations. The AUC0–12 h for the S(+) enantiomer was significantly higher than for the R(–) enantiomer (Table 1). The mean plasma concentration–time profile of ketoprofen after rectal administration of 1 g ketoprofen in a fatty suppository base is shown in Fig 1. There were no visible residues of the rectally administered suppositories in the faecal material 1 hour after administration. Bioavailability after rectal administration was low. The Cmax value and the AUC0–12 h value were significantly higher for the S(+) than for the R(–) enantiomer (Student’s t-test for paired data, P<0·05) (Table 1). Landoni and Lees (1995b) found AUC0-∝ values of 4·38 µg h ml–1 for the S(+) enantiomer and 2·95 µg h ml–1 for the R(–) KTP after IV administration of 2·2 mg kg–1 racemic KTP to horses. The variation between these results and the results described above can probably be attributed to inter-animal differences that can arise in drug pharmacokinetics. In spite of these differences, the present data confirm the results of Landoni and Lees (1995b) and Jaussaud et al (1993) who concluded that enantioselective pharmacokinetics of racemic KTP occurs in horses. Aboul-Enein et al (1998) also confirmed the observation that bio-inversion of R(–) ketoprofen to the S(+) isomer is significant in the equine species. As there was no significant difference in bioavailability between the two enantiomers [the ratio of the AUCIV for S:R (1·46) was not different to that for the rectal treatment (1·5)], it is assumed that no pre-systemic inversion from R(–) to S(+) occurs after rectal administration of racemic KTP to horses. Landoni and Lees (1995b) found an oral bioavailability of 2·67 ± 0·43 and 5·75 ± 1·48 per cent for R(–) and S(+) enantiomers for a KTP oil-based paste at a dose of 2·2 mg kg–1, and a bioavailability of 50·50 ± 10·95 and 54·17 ± 9·9 per cent for R(–) and S(+) enantiomers after oral administration of KTP powder (in capsules). The bioavailability of
1 0.8 0.6 0.4 0.2 0 0
2
4
6
Time (h) FIG 1: The drug plasma concentration-time profiles of the R(–) enantiomer and S(+) enantiomer following rectal administration of 1 g racemic KTP. ■, S(+) KTP; ▲, R(–) KTP
racemic KTP from a fatty suppository base was 28 ± 12·3 and 28 ± 12·4 per cent for R(–) and S(+) KTP, respectively and therefore lower than that of KTP powder in capsules but higher than the bioavailability of the oil-based paste. There is a strong indication that a significant bio-inversion of R(–) KTP to the S(+) isomer takes place in horses. This bio-inversion is similar after both IV and rectal administration. As there is no significant difference in bioavailability between the two enantiomers, it is assumed that no pre-systemic inversion from R(–) to S(+) occurs after rectal administration of racemic KTP to horses.
ACKNOWLEDGEMENTS G. Van der Weken and W. Baeyens wish to thank Merck Belgolabo (Brussels, Belgium) for the use of their instruments and the technical support.
REFERENCES ABOUL-ENEIN, H. Y., VAN OVERBEKE, A., VAN DER WEKEN, G., BAEYENS, W., ODA, H., DEPREZ, P. & DE KRUIF, A. (1998) HPLC on Chiralcel OJ-R for enantiomer separation and analysis of ketoprofen, from horse plasma, as the 9aminophenanthrene derivative. Journal Pharmacy and Pharmacology 50, 291–296. CORVELEYN, S., DEPREZ, P., VAN DER WEKEN, G., BAEYENS, W. & REMON, J.P. (1996) Bioavailability of ketoprofen in horses after rectal administration. Journal of Veterinary Pharmacology and Therapeutics 19, 359–363. IWAKAWA, S., HE, X., HASHIMOTO, S., VOLLAND, C., BENET, L. Z. & LIN, E. T. (1991) Stereoselective disposition of ketoprofen in rats. Drug Metabolism and Disposition 19, 717–719. JAMALI, F., LOVLIN, R. & ABERG, G. (1997) Bi-directional chiral inversion of ketoprofen in CD-1 mice. Chirality 9, 29–31. JAUSSAUD, P., BELLON, C., BESSE, S., COURTOT, D. & DELATOUR, P. (1993) Enantioselective pharmacokinetics of ketoprofen in horses. Journal of Veterinary Pharmacology and Therapeutics 16, 373–376. KING, C. (1994) Rectal drug administration. Journal of Equine Veterinary Science 14, 521–526. LANDONI, M. F. & LEES, P. (1995a) Pharmacokinetics and pharmacodynamics of ketoprofen enantiomers in calves. Chirality 7, 586–597. LANDONI, M. F. & LEES, P. (1995b) Influence of formulation on the pharmacokinetics and bioavailability of racemic ketoprofen in horses. Journal of Veterinary Pharmacology and Therapeutics 18, 446–450. SALLUSTIO, B. C., PURDIE, Y. J., WHITEHEAD, A. G., AHERN, M. J. & MEFFIN, P. J. (1988) The disposition of ketoprofen enantiomers in man. British Journal of Clinical Pharmacology 26, 765–770. STEEL, C. M., BOLTON, J. R., PRECHAGOON, Y. & CHARLES, B. G. (1999) Unreliable rectal absorption of cisapride in horses. Equine Veterinary Journal 31(1), 82–84. Accepted April 21, 1999
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Bioavailability of racemic ketoprofen in healthy horses following rectal administration S. CORVELEYN*, D. HENRIST*, J.P. REMON*, G. VAN DER WEKEN†, W. BAEYENS†, J. HAUSTRAETE†, H.Y. ABOUL-ENEIN‡, B. SUSTRONCK§, P. DEPREZ§
*Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of Gent, Harelbekestraat 72, 9000 Gent, Belgium, †Laboratory of Drug Analysis, Faculty of Pharmaceutical Sciences, University of Gent, Harelbekestraat 72, 9000 Gent, Belgium, ‡Biological and Medical Research Department, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi-Arabia, §Department of Internal Diseases of Large Animals, Faculty of Veterinary Medicine, University of Gent, Salisburrylaan 133, 9820 Merelbeke, Belgium SUMMARY Ketoprofen (KTP) is a chiral non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class, approved by the FDA for the allevation of pain associated with musculoskeletal disorders in horses. The present study was designed to examine the bioavailability of ketoprofen enantiomers after rectal administration of the racemate to healthy horses. One gram of racemic ketoprofen was injected intravenously and administered rectally as a fat based suppository in a cross-over design study (n = 4). Blood samples were analysed for KTP enantiomers using HPLC. After IV administration, the S(+) enantiomer concentrations in plasma were higher than the R(–) enantiomer concentrations and the AUC0–12 h for the S(+) enantiomer was significantly higher than for the R(–) enantiomer. Following rectal administration Cmax and AUC0–12 h were significantly higher for the S(+) than for the R(–) enantiomer. Bioavailability after rectal administration was low. Since there was no significant difference in bioavailability between the two enantiomers, it is assumed that no pre-systemic inversion from R(–) to S(+) occurred after rectal administration of racemic KTP to horses. © 1999 Harcourt Publishers Limited
KETOPROFEN (KTP) is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class. It is a chiral molecule, existing as two enantiomers, S(+) and R(–) KTP. The recommended maximal dose for horses is 2·2 mg kg–1 body weight daily for a maximum of 5 days. The clinical application of rectal drug administration in horses has received little attention in the past. The lack of data on rectal absorption of drugs in horses, the lack of patient cooperation and the voluminous faecal production of herbivores such as the horse had a negative influence on the development of drug products for rectal administration (King 1994). However, there are indications for using this route of administration such as when the oral administration of medication is difficult due to non-compliance of patient or when gastrointestinal motility is severely impaired. In addition the oral route can not be used in some patients due to oral or oesophageal injuries or ulceration and in convulsing neonates rectal administration is easier than parenteral or oral administration (King 1994). In a previous study (Corveleyn et al 1996) the rectal bioavailability of ketoprofen in healthy horses was evaluated using two different suppository bases and one liquid suspension. It was reported that the absolute bioavailability of KTP in horses after rectal administration was relatively low (24·5 to 31·3 per cent) for the different formulations, with a large interindividual variability. This was also reported for rectally administered cisapride (Steel et al 1999). A number of studies have looked at the enantioselective pharmacokinetics of racemic KTP in man (Sallustio et al 1988) and various animal species including rats (Iwakawa et al 1991), mice (Jamali et al 1997), calves (Landoni and Lees 1995a) and horses (Landoni and
Corresponding author: J.P. Remon. Tel: ++32 9 264 80 54 Fax: ++32 9 222 82 36 E-mail: [email protected] 0034-5288/99/050201 + 02 $18.00/0
Lees 1995b). It was the objective of this study to examine the bioavailability of ketoprofen enantiomers after rectal administration of the racemate to horses. Four healthy mares with ages ranging from 6 to 12 years and weighing 415 to 540 kg were used in this study. The horses were fed 2 kg concentrate a day and had free access to hay and straw. Water was available ad libitum. An IV solution containing 10 per cent (w/v) racemic ketoprofen (Ketofen®, Rhone Mérieux, Lyon, France) and a suppository formulation containing 1 g of micronised racemic ketoprofen (Sigma Chemical Co, St. Louis, USA) in a hard fatty base (Witepsol H15, Hüls AG, Witten, Germany) were administered in a cross-over design study. A time interval of at least 1 week was allowed to elapse between each administration. The animals were fitted with an IV catheter at the beginning of the experiment. Blood samples (5 ml) were taken 5 minutes before and at predetermined time intervals after IV and rectal administration. Blood samples were collected in vacuum tubes (Venoject®, Kimble-Terumo, Elkton, MA, USA) containing heparin as an anticoagulant. Plasma was separated by centrifugation at 2000 g for 2 minutes and stored at –20°C until analysed. In order to analyse the KTP enantiomers in horse plasma a new HPLC method based on the application of an alkyl-diol-silica precolumn was developed and validated (Baeyens et al unpublished data). All reagents and instrumentation were from Merck (Darmstadt, Germany). The plasma samples, buffered with phosphate buffer (pH 7·0) were brought or to the pre-column (C 18 alkyl-diol-silica (ADS), 25 µm, 25 × 4 mm ID) by means of a six-port valve using a 0·1 M phosphate buffer, pH 7·0. After washing with the buffer for at least 11 minutes, the ADS-column was backflushed (flow rate 0·6 mL min–1) with the mobile phase (0·01 M phosphate buffer – 6 per cent (v/v) 2-propanol – 5 mM octanoic acid at pH 5·5), thus transporting the analytes over a chiral human serum albumin (HSA) 100 × 4·0 mm column (Advanced Separation Technologies Inc., © 1999 Harcourt Publishers Limited
202 S. Corveleyn, D. Henrist, J.P. Remon, G. Van der Weken, W. Baeyens, J. Haustraete, H.Y. Aboul-Enein, B. Sustronck, P. Deprez
TABLE 1: Bioavailability of S(+) KTP and R(–) KTP in horse plasma after a single IV dose and a rectal administration of 1 g rac-KTP (N=4). Mean (S.D.) Parameter
1. IV dose AUC0–12 h (µg.h/ml) 2. Rectal administration AUC0–12 h (µg.h/ml) Cmax (µ g/ml) Tmax (h) F (%)
S(+)KTP
R(–)KTP
6·7a (1·45)
4·6 (1·07)
1·8a (0·52) 1·05a (0·336) 1 (0·0) 28 (12·4)
1·2 (0·31) 0·78 (0·253) 0·9 (0·25) 28 (12·3)
a Significantly higher than R(–) enantiomer (Student’s t-test for paired data, P < 0·05).
1.4 1.2 Concentration (ug ml–1)
New Jersey, USA) provided with a guard column 10 × 3·0 mm (kept at 30°C) where the separation of the KTP enantiomers (resolution 1·4) was achieved with UV detection at 260 nm. The limit of detection in plasma was 7 ng ml–1 for S(+) and 10 ng ml–1 for R(–) ketoprofen. Intra-assay variability (N=10) was between 1·4 and 2·8 per cent. Linearity and recovery for S(+) and R(–) KTP were in the ranges 0·9988 to 0·9999 and 92·1 to 102·0 per cent, respectively. The individual concentration-time profiles were analysed by MW/PHARM version 3·0 (Mediware 1987–1991, Utrecht, The Netherlands). The IV data fitted a two-compartment model (r2=0·99). The AUC0–12 h were calculated using the logarithmic and linear trapezoidal rules. The maximum plasma ketoprofen concentration (Cmax) and the time to reach the maximum plasma concentration (tmax) following rectal administration were determined from the individual plasma concentration-time profiles. F is a measure for the amount of drug absorbed, expressed as a percentage of the dose. All results are presented as mean ± SD. Data were analysed statistically by use of the Student’s t-test for paired data; the level of significance was P<0·05. The drug plasma concentration-time profile following IV dosing was described by a two-compartment open model. After IV administration, the R(–) enantiomer concentrations were lower compared to the S(+) enantiomer concentrations. The AUC0–12 h for the S(+) enantiomer was significantly higher than for the R(–) enantiomer (Table 1). The mean plasma concentration–time profile of ketoprofen after rectal administration of 1 g ketoprofen in a fatty suppository base is shown in Fig 1. There were no visible residues of the rectally administered suppositories in the faecal material 1 hour after administration. Bioavailability after rectal administration was low. The Cmax value and the AUC0–12 h value were significantly higher for the S(+) than for the R(–) enantiomer (Student’s t-test for paired data, P<0·05) (Table 1). Landoni and Lees (1995b) found AUC0-∝ values of 4·38 µg h ml–1 for the S(+) enantiomer and 2·95 µg h ml–1 for the R(–) KTP after IV administration of 2·2 mg kg–1 racemic KTP to horses. The variation between these results and the results described above can probably be attributed to inter-animal differences that can arise in drug pharmacokinetics. In spite of these differences, the present data confirm the results of Landoni and Lees (1995b) and Jaussaud et al (1993) who concluded that enantioselective pharmacokinetics of racemic KTP occurs in horses. Aboul-Enein et al (1998) also confirmed the observation that bio-inversion of R(–) ketoprofen to the S(+) isomer is significant in the equine species. As there was no significant difference in bioavailability between the two enantiomers [the ratio of the AUCIV for S:R (1·46) was not different to that for the rectal treatment (1·5)], it is assumed that no pre-systemic inversion from R(–) to S(+) occurs after rectal administration of racemic KTP to horses. Landoni and Lees (1995b) found an oral bioavailability of 2·67 ± 0·43 and 5·75 ± 1·48 per cent for R(–) and S(+) enantiomers for a KTP oil-based paste at a dose of 2·2 mg kg–1, and a bioavailability of 50·50 ± 10·95 and 54·17 ± 9·9 per cent for R(–) and S(+) enantiomers after oral administration of KTP powder (in capsules). The bioavailability of
1 0.8 0.6 0.4 0.2 0 0
2
4
6
Time (h) FIG 1: The drug plasma concentration-time profiles of the R(–) enantiomer and S(+) enantiomer following rectal administration of 1 g racemic KTP. ■, S(+) KTP; ▲, R(–) KTP
racemic KTP from a fatty suppository base was 28 ± 12·3 and 28 ± 12·4 per cent for R(–) and S(+) KTP, respectively and therefore lower than that of KTP powder in capsules but higher than the bioavailability of the oil-based paste. There is a strong indication that a significant bio-inversion of R(–) KTP to the S(+) isomer takes place in horses. This bio-inversion is similar after both IV and rectal administration. As there is no significant difference in bioavailability between the two enantiomers, it is assumed that no pre-systemic inversion from R(–) to S(+) occurs after rectal administration of racemic KTP to horses.
ACKNOWLEDGEMENTS G. Van der Weken and W. Baeyens wish to thank Merck Belgolabo (Brussels, Belgium) for the use of their instruments and the technical support.
REFERENCES ABOUL-ENEIN, H. Y., VAN OVERBEKE, A., VAN DER WEKEN, G., BAEYENS, W., ODA, H., DEPREZ, P. & DE KRUIF, A. (1998) HPLC on Chiralcel OJ-R for enantiomer separation and analysis of ketoprofen, from horse plasma, as the 9aminophenanthrene derivative. Journal Pharmacy and Pharmacology 50, 291–296. CORVELEYN, S., DEPREZ, P., VAN DER WEKEN, G., BAEYENS, W. & REMON, J.P. (1996) Bioavailability of ketoprofen in horses after rectal administration. Journal of Veterinary Pharmacology and Therapeutics 19, 359–363. IWAKAWA, S., HE, X., HASHIMOTO, S., VOLLAND, C., BENET, L. Z. & LIN, E. T. (1991) Stereoselective disposition of ketoprofen in rats. Drug Metabolism and Disposition 19, 717–719. JAMALI, F., LOVLIN, R. & ABERG, G. (1997) Bi-directional chiral inversion of ketoprofen in CD-1 mice. Chirality 9, 29–31. JAUSSAUD, P., BELLON, C., BESSE, S., COURTOT, D. & DELATOUR, P. (1993) Enantioselective pharmacokinetics of ketoprofen in horses. Journal of Veterinary Pharmacology and Therapeutics 16, 373–376. KING, C. (1994) Rectal drug administration. Journal of Equine Veterinary Science 14, 521–526. LANDONI, M. F. & LEES, P. (1995a) Pharmacokinetics and pharmacodynamics of ketoprofen enantiomers in calves. Chirality 7, 586–597. LANDONI, M. F. & LEES, P. (1995b) Influence of formulation on the pharmacokinetics and bioavailability of racemic ketoprofen in horses. Journal of Veterinary Pharmacology and Therapeutics 18, 446–450. SALLUSTIO, B. C., PURDIE, Y. J., WHITEHEAD, A. G., AHERN, M. J. & MEFFIN, P. J. (1988) The disposition of ketoprofen enantiomers in man. British Journal of Clinical Pharmacology 26, 765–770. STEEL, C. M., BOLTON, J. R., PRECHAGOON, Y. & CHARLES, B. G. (1999) Unreliable rectal absorption of cisapride in horses. Equine Veterinary Journal 31(1), 82–84. Accepted April 21, 1999