Stereoselective Pharmacokinetics of Ketoprofen After Oral Administration of Modified-Release Formulations in Caucasian Healthy Subjects.

BACKGROUND AND OBJECTIVES: Ketoprofen, a potent nonsteroidal anti-inflammatory drug, is clinically administered as a racemic mixture. One of the possible metabolism routes of ketoprofen is the inversion of the R- to S-enantiomer in the gastrointestinal tract. Ketoprofen, as a weak acid drug, might undergo recirculation through pancreatic/intestinal juices. The aim of the work was to investigate if a plasma-gastrointestinal tract recirculation of ketoprofen could explain its R-to-S chiral inversion after the oral administration of two modified-release formulations: a gastro-resistant delayed-release tablet (Reference) and an extended-release-plus-immediate-release bilayer tablet (Test). METHODS: Sixteen healthy Caucasian volunteers (eight women and eight men) participated in a ketoprofen bioequivalence study. Both formulations were administered with and without food. In both cases, standard meals were given throughout the experiment. R- and S-enantiomers were measured separately using a validated HPLC-UV chiral method. Mean concentration-time profiles of ketoprofen enantiomers in plasma were obtained for men and women. Area under the plasma concentration-time curve, maximum ketoprofen plasma concentration, and time-to-peak were also computed for both isomers, both modes of administration, and both sexes. S/R concentration ratio was assessed as an indicator of enantiomer chiral inversion rate. RESULTS: Differences in the pharmacokinetics of S- and R-ketoprofen enantiomers were found after the Test administration. S-Ketoprofen presented a lower plasma exposure compared to R-enantiomer. However, the S/R concentration ratio increased 1 h (in men) and 2 h (in women) after meal intakes. This was related to pancreatic and/or intestinal and/or biliary secretions of the drug, followed by reabsorption and conversion of the R- to the S-isomer. The lower intestinal pH reported for men would lead to a higher oral bioavailability of the Test formulation and a higher reabsorption of both ketoprofen isomers in this sex. Hence, a higher rise of the S/R concentration ratio could be observed in men. No significant differences between isomers exposure were detected in both sexes after the Reference administration. Different lag times were observed after fed and fasting administration of this formulation; however, drug absorption coincided with food ingestion. Then, drug recirculation affected the S/R ratio from the beginning of drug exposure, minimizing the difference between isomers disposition. CONCLUSIONS: R-to-S conversion rate could be mainly associated with several passages of the drug through the intestinal mucosa. The concentration-time profiles of ketoprofen in plasma after the administration of both formulations evidenced R-to-S conversion of recirculating drug following meal intakes.

Hematological parameters in cows in early lactation treated with ketoprofen and their relationship with lipid mobilization and ketogenesis

Background: Dairy cows are exposed to numerous hematological and biochemical changes, what is bringing cows into the state of increased metabolic activity and physiological adaptations. These adaptive processes have resulted in increased lipid mobilization and ketogenesis with increased concentration of non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHB). As a non steroidal anti-inflammatory drug, ketoprofen produces anti-inflammatory effects. The main objective of the present study was to found relationship between hematological parameters and ketoprofen administration and high lipid mobilization and ketogenesis in cows treated with ketoprofen immediately after calving. Materials, Methods & Results: Ketoprofen was used (3 mg/kg body weight) intramuscularly for three consecutive days post-partum on 15 cows of Holstein-Friesian breed. Cows of the control group (n = 15) were not treated with ketoprofen. Blood samples were collected at the day of calving, in the first and in the second week after parturition from the coccygeal vein of the both groups. Hematological parameters (erythrocytes, hemoglobin, neutrophils, lymphocytes and mean platelet volume) were determined on the automatic hematological counter. Metabolic parameters (NEFA, BHB) were determined by standard colorimetric kits using a semi-automatic biochemistry analyzer. Students t-test was used to [...]

Hematological parameters in cows in early lactation treated with ketoprofen and their relationship with lipid mobilization and ketogenesis

Background: Dairy cows are exposed to numerous hematological and biochemical changes, what is bringing cows into the state of increased metabolic activity and physiological adaptations. These adaptive processes have resulted in increased lipid mobilization and ketogenesis with increased concentration of non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHB). As a non steroidal anti-inflammatory drug, ketoprofen produces anti-inflammatory effects. The main objective of the present study was to found relationship between hematological parameters and ketoprofen administration and high lipid mobilization and ketogenesis in cows treated with ketoprofen immediately after calving. Materials, Methods & Results: Ketoprofen was used (3 mg/kg body weight) intramuscularly for three consecutive days post-partum on 15 cows of Holstein-Friesian breed. Cows of the control group (n = 15) were not treated with ketoprofen. Blood samples were collected at the day of calving, in the first and in the second week after parturition from the coccygeal vein of the both groups. Hematological parameters (erythrocytes, hemoglobin, neutrophils, lymphocytes and mean platelet volume) were determined on the automatic hematological counter. Metabolic parameters (NEFA, BHB) were determined by standard colorimetric kits using a semi-automatic biochemistry analyzer. Students t-test was used to [...](AU)

A pharmacokinetic comparison of meloxicam and ketoprofen following oral administration to healthy dogs.

Ketoprofen (KTP) and meloxicam (MLX) are non-steroidal anti-inflamatory drugs used extensively in veterinary medicine. The pharmacokinetics of these drugs were studied in eight dogs following a single oral dose of 1 mg/kg of KTP as a racemate or 0.2 mg/kg of MLX. The concentrations of the drugs in plasma were determined by high-performance liquid chromatography (HPLC). There were differences between the disposition curves of the KTP enantiomers, confirming that the pharmacokinetics of KTP is enantioselective. (S)-(+)-KTP was the predominant enantiomer; the S:R ratio in the plasma increased from 2.58 +/- 0.38 at 15 min to 5.72 +/- 2.35 at 1 h. The area under the concentration time curve (AUC) of (S)-(+)-KTP was approximately 6 times greater than that of (R)-(-)-KTP. The mean (+/- SD) pharmacokinetic parameters for (S)-(+)-KTP were characterized as Tmax = 0.76 +/- 0.19 h, Cmax = 2.02 +/- 0.41 microg/ml, t1/2el = 1.65 +/- 0.48 h, AUC = 6.06 +/- 1.16 microg.h/ml, Vd/F = 0.39 +/- 0.07 L/kg, Cl/F = 170 +/- 39 ml/(kg.h). The mean (+/- SD) pharmacokinetic parameters of MLX were Tmax = 8.5 +/- 1.91 h, Cmax = 0.82 +/- 0.29 microg/ml, t1/2lambda(z) = 12.13 +/- 2.15 h, AUCinf = 15.41 +/- 1.24 microg.h/ml, Vd/F = 0.23 +/- 0.03 L/ kg, and Cl/F = 10 +/- 1.4 ml/(kg.h). Our results indicate significant pharmacokinetic differences between MLX and KTP after therapeutic doses.

Some pharmacokinetic parameters of R-(-)- and S-(+)-ketoprofen: the influence of age and differing physiological status in dairy cattle.

The pharmacokinetic parameters of ketoprofen have previously been studied in cattle, but no studies have been performed on differing ages and metabolic situations in these animals. The aim of this work was to study the possible modifictions of the pharmacokinetics of ketoprofen enantiomers that may result from age, lactation or gestation in dairy cattle. Three groups of Holando Argentino cattle contained, respectively, 8 cows in early lactation, 8 pregnant cows and 8 newborn calves. Four animals from each group received the enantiomer R-(-)-ketoprofen, the other four animals received the S-(+) enantiomer, all by intravenous injection at a dose of 0.5 mg/kg. Significant differences between the three categories of animals were obtained in elimination half-life (t1/2) (1.52, 0.87 and 0.31 and 1.71, 0.69 and 0.26 in newborn calves, cows in early lactation and cows in gestation, respectively), mean residence time (MRT) (0.45, 1.25, 2.20 and 0.38, 0.99, 2.47 h, in cows in gestation, cows in early lactation and newborn calves, respectively) and area under the plasma concentration-time curve (AUC) (0.87, 2.93, 3.24, and 0.67, 2.78, 5.13 (microg/h)/ml in cows in gestation, cows in early lactation and newborn calves, respectively, for the R-(-) and S-(+) enantiomer, respectively. In calves, there was a significant difference in AUC (3.24 vs 5.13 (microg/h)/ml between R-(-)- and S-(+)-ketoprofen. In view of the differences between calves and adult cattle in the pharmacokinetic results for ketoprofen, the effects of age and physiological status (lactation, gestation) should be taken into account for therapeutic regimens.

Chiral inversion of (R)-ketoprofen: influence of age and differing physiological status in dairy cattle.

The chiral inversion of ketoprofen has been previously demonstrated in cattle, but no studies have been performed on different ages and metabolic situations in the animals. The aim of this work was to study any modifications of the stereoconversion of ketoprofen that occur by reason of age, lactation or gestation in dairy cows. Holando Argentino cattle were divided into three groups: 8 cows in early lactation, 8 pregnant cows and 8 newborn calves. Four animals from each group received the enantiomer R-(-)-ketoprofen by intravenous administration; the other four animals received the S-(+) enantiomer, all at doses of 0.5 mg/kg. Blood samples were collected at standardized times after dosing and assayed for ketoprofen by high-performance reversed-phase liquid chromatography (HPLC). The percentage inversion of R-(-)-ketoprofen to S-(+)-ketoprofen was 50.5% (SD +/- 2.4) in the preruminants, 33.3% (SD +/- 1.7) in cows in early lactation and 26.0% (SD +/- 5.1) in cows in gestation. These results indicate a differing enantioselective metabolic behaviour for one compound in one species under different physiological situations.

Enantiospecific pharmacokinetics of ketoprofen in plasma and synovial fluid of horses with acute synovitis.

Pharmacokinetic parameters were established for enantiomers of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen (KTP) administered as the racemic mixture at a dose of 2.2 mg/kg and as separate enantiomers, each at a dose of 1.1 mg/kg to a group of six horses (five mares and one gelding). A four-period cross-over study in a LPS-induced model of acute synovitis was used. After administration of the racemic mixture S(+)KTP was the predominant enantiomer in plasma as well as in synovial fluid. Unidirectional inversion of R(-) to S(+)KTP was demonstrated but the inversion was less marked than previously reported. It is suggested that this reduction could be because of the influence of the inflammatory reaction on hepatic metabolism. The disposition of KTP enantiomers after administration of the racemic mixture was similar to those observed after administration of S(+) and R(-)KTP. The S(+) and R(-)KTP concentrations in synovial fluid were low and short lasting. After administration of R(-)KTP significant concentrations of the optical antipode were detected in synovial fluid.