title: Stereoselective Pharmacokinetics of Ketoprofen After Oral Administration of Modified-Release Formulations in Caucasian Healthy Subjects.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.|Bioavailability and Bioequivalence Centre for Medicine Evaluation, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.
authors.forename: Marianela
authors.initials: M
authors.lastname: Lorier
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.|Bioavailability and Bioequivalence Centre for Medicine Evaluation, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.
authors.forename: Laura
authors.initials: L
authors.lastname: Magallanes
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.|Bioavailability and Bioequivalence Centre for Medicine Evaluation, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ibarra
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.|Bioavailability and Bioequivalence Centre for Medicine Evaluation, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.
authors.forename: Natalia
authors.initials: N
authors.lastname: Guevara
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.|Bioavailability and Bioequivalence Centre for Medicine Evaluation, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay.
authors.forename: Marta
authors.initials: M
authors.lastname: Vázquez
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Chemistry, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay. pfagioli@fq.edu.uy.|Bioavailability and Bioequivalence Centre for Medicine Evaluation, Universidad de la República, P. O. Box 1157, 11800, Montevideo, Uruguay. pfagioli@fq.edu.uy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Fagiolino
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D018592:Cross-Over Studies; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics; D004339:Drug Compounding; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D007660:Ketoprofen / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D015394:Molecular Structure; D012727:Sex Characteristics; D013237:Stereoisomerism; D013608:Tablets, Enteric-Coated; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D003692:Delayed-Action Preparations; D013608:Tablets, Enteric-Coated; D007660:Ketoprofen