Pharmacokinetics of ketoprofen enantiomers in monkeys following single and multiple oral administration

Mauleón, David; Mis, R.; Ginesta, Joan; Ortega, Elvira; Vilageliu, J; Basi, N; Carganico, Germano

doi:10.1002/chir.530060705

Cited by 19 publications

(6 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After administration of racemic KP to camels, we have observed a predominance of R-KP, a phenomena that is shared with sheep (Delatour et al, 1993). This, however, contrasts with the findings reported in other species like humans, rats, rabbits, calves, dogs, cats, monkeys and horses, where S-KP is predominant and has been attributed to unidirectional inversion of R-KP to S-KP (Abas & Meffin, 1987;Foster & Jamali, 1988;Jamali & Brocks, 1990;Iwakawa et al, 1991;Delatour et al, 1993;Benoit et al, 1994;Mauleon et al, 1994;Landoni & Lees, 1995a,b, 1996. We cannot ascertain in this study whether there was a chiral inversion in camels because we have not administered the individual enantiomers.…”

Section: Discussionmentioning

confidence: 72%

Pharmacokinetics of ketoprofen enantiomers after intravenous administration of racemate in camels: effect of gender

Katheeri

Wasfi

Lambert

et al. 2000

Vet Pharm & Therapeutics

View full text Add to dashboard Cite

The pharmacokinetics of ketoprofen (KP) enantiomers were studied in ten female and eight male camels after a single intravenous dose (2.0 mg/kg) of racemic KP. A high performance liquid chromatographic (HPLC) method was developed for the quantitation of the R- and S-enantiomers without derivatization of the samples using a S,S-Whelk-01 chiral stationary phase column. The data collected (median and range) were as follows: the areas under the curve to infinity (AUC) (microg/mL per h) were 22.4 (13.5-29.7) and 19.8 (13.8-22.1) for R- and S-KP, respectively, in female camels while the corresponding values in male camels were 16.0 (12.9-22.4) and 14.4 (11.0-19.3). In both sexes, the AUC for the R-enantiomer was significantly larger than that of the S-enantiomer. Total body clearances (Cl(t)) were 44.6 (33.7-74.1) and 50.6 (45.2-72.4) mL/kg per h for R- and S-KP, respectively, in female camels and were 62.8 (44.6-77.8) and 69.6 (51.8-91.1) mL/kg per h for R- and S-KP, respectively, in male camels. In both sexes of camels, the Cl(t) values for R-KP were significantly lower than its corresponding antipode. The steady-state volumes of distribution (Vss) were 97.9 (82.8-147.2) and 102.0 (90.1-169.0) mL/kg for R- and S-KP, respectively, in female camels and were significantly different from each other, while the respective values in male camels were 151.5 (105.3-222.3) and 154.0 (114.7-229.0) mL/kg but were not significantly different from each other. The volumes of distribution (area) followed a similar pattern, where the values for R- and S-KP in female camels were 118.5 (95.6-195.2) and 137.6 (115.8-236.2) mL/kg, respectively, and the respective values in male camels were 215.6 (119.1-270.1) and 229.1 (143.3-277.4) mL/kg. The elimination half-lives (t1/2beta) were 1.88 (1.42-2.34) h and 1.83 (1.67-2.26) h for R- and S-KP, respectively, in female camels and were significantly different from each other, while the corresponding values in male camels were 2.11 (1.50-4.20) and 2.33 (1.52-3.83) h for R and S-KP, respectively, but were not significantly different from each other. The mean residence time followed a similar pattern. All pharmacokinetic parameters for R- and S-KP in female camels were significantly different from their corresponding values in male camels. The extent of protein binding for R- and S-KP was evaluated in vitro by ultrafiltration. The extents of protein binding for R- and S-KP were not significantly different from each other when each enantiomer was supplemented separately. However, when the enantiomers were supplemented together, protein binding of R-KP was significantly higher than that of S-KP in female but not in male camels.

show abstract

Section: Discussionmentioning

confidence: 72%

Pharmacokinetics of ketoprofen enantiomers after intravenous administration of racemate in camels: effect of gender

Katheeri

Wasfi

Lambert

et al. 2000

Vet Pharm & Therapeutics

View full text Add to dashboard Cite

show abstract

“…The present study demonstrates enantioselective pharmacokinetics of KTP in sheep, R(–)KTP being the predominant enantiomer in plasma, exudate and transudate. Enantioselective pharmacokinetics for KTP have previously been reported in several animal species, including humans ( Rudy et al ., 1998 ), monkeys ( Mauleon et al ., 1994 ), rats ( Tamai et al ., 1991 ); horses ( Landoni & Lees, 1996); calves ( Landoni & Lees, 1995b); sheep ( Delatour et al ., 1993 ; Kadir & Lees, 1997a); rabbits ( Abas & Meffin, 1987) dogs ( Delatour et al ., 1993 ) and cats ( Delatour et al ., 1993 ; Kadir, 1998).…”

Section: Discussionmentioning

confidence: 99%

Enantiospecific pharmacokinetics and pharmacodynamics of ketoprofen in sheep

Landoni

Comas²,

Mucci³

et al. 1999

Vet Pharm & Therapeutics

View full text Add to dashboard Cite

Pharmacokinetic and pharmacodynamic parameters were established for the enantiomers of the 2-arylpropionic acid (APA) nonsteroidal anti-inflammatory drug (NSAID), ketoprofen (KTP). Each enantiomer was administered separately (1.5 mg/kg) and in a racemic mixture (3 mg/kg) intravenously (i.v.) to a group of eight sheep in a four-way, four-period cross-over study using a tissue cage model of inflammation. Plasma disposition of each KTP enantiomer was similar following separate administration of the pure compounds compared to administration of the racemic mixture. S(+)KTP volume of distribution (Vd(area)) was higher and clearance (ClB) faster than those of R(-)KTP. S(+) and R(-)KTP achieved relatively low concentrations in exudate and transudate. Unidirectional limited chiral inversion of R(-) to S(+)KTP was demonstrated. After R(-)KTP administration S(+)KTP was detected in plasma, but not in either exudate or transudate. Pharmacokinetic/pharmacodynamic (PK/PD) modelling of the data could not be undertaken following R(-)KTP administration because of chiral inversion to S(+)KTP, but the pharmacodynamic parameters, calculated maximum effect (Emax), concentration producing 50% effect (EC50), Hill's coefficient (N), rate constant of elimination of drug effect from the compartment (KeO) and mean equilibration half-life (t1/2KeO) were determined for S(+)KTP after administration of the racemic mixture as well as the pure compound.

show abstract

“…In rabbits, the metabolic inversion of RKP is limited to 9-12% after administration of the racemic.zs In Cynomolgus monkeys, inversion of RKP is 49%. 26 In humans, the inversion is no more than 10%. 27 • 28 These data support a high interspecies variability in the inversion process.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive Effects of S(+)‐Ketoprofen and Other Analgesic Drugs in a Rat Model of Pain Induced Uric Acid

López‐Muñoz

Ventura

Díaz

et al. 1998

The Journal of Clinical Pharma

View full text Add to dashboard Cite

We investigated the antinociceptive properties of dexketoprofen trometamol (S(+)-ketoprofen tromethamine salt; SKP), a new analgesic, antiinflammatory drug, using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. SKP was compared with racemic ketoprofen tromethamine salt (rac-KP), R(-)-ketoprofen tromethamine salt (RKP), ketorolac (KET), and morphine (MOR). We also assessed the effects of flurbiprofen (rac-FB) and its enantiomers (SFB and RFB) in the same model. Groups of six rats received either vehicle or analgesic drug and antinociception was evaluated by evaluating the dose-response curves over time. SKP was an effective antinociceptive drug in this model and was almost equally potent by either oral or intracerebroventricular administration. The oral potency of SKP was similar to that of oral KET and greater than that of oral MOR. No significant differences were observed between racemic ketoprofen and its enantiomers when administered orally. In the rat, significant bioinversion of RKP to SKP occurs when RKP is given orally. After oral administration of RKP, SKP was detectable in 30 min and surpassed the concentration of RKP after 3 h. Nevertheless, when the compounds were given intracerebroventricularly, some stereoselectivity in favor of SKP was observed. Stereoselectivity was observed with flurbiprofen, an analogue of ketoprofen that does not undergo significant metabolic inversion. Whereas SFB was an effective antinociceptive, RFB had no antinociceptive effect at the doses tested when given either orally or intracerebroventricularly.

show abstract

Pharmacokinetics of ketoprofen enantiomers in monkeys following single and multiple oral administration

Cited by 19 publications

References 10 publications

Pharmacokinetics of ketoprofen enantiomers after intravenous administration of racemate in camels: effect of gender

Pharmacokinetics of ketoprofen enantiomers after intravenous administration of racemate in camels: effect of gender

Enantiospecific pharmacokinetics and pharmacodynamics of ketoprofen in sheep

Antinociceptive Effects of S(+)‐Ketoprofen and Other Analgesic Drugs in a Rat Model of Pain Induced Uric Acid

Contact Info

Product

Resources

About