Journal of APPLIED BIOMEDICINE
ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)

Volume 4 (2006), No 3, p 153-161




Enantiospecific pharmacokinetic studies on ketoprofen in tablet formulation using indirect chiral HPLC analysis

Kannappan Valliappan, Kamarajan Kannan, Thanikachalam Sivakumar, Rajappan Manavalan

Address: Kannappan Valliappan, Department of Pharmacy, Faculty of Engineering and Technology, Annamalai University, Annamalainagar, TN 608 002, India
kvalliappan@gmail.com

Received 21st February 2006.
Revised 23rd March 2006.
Published online 2nd June 2006.

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SUMMARY
The present study was undertaken to evaluate the possibility of chiral discrimination in the release of enantiomers of ketoprofen (KT) in tablet form and, in turn, the bioavailability of the individual enantiomers, using the rabbit as a model. The enantiomeric concentration of KT in plasma was determined using a customized chiral HPLC analysis. First the plasma concentration-time profile was established for pure (±) KT in order to assess the extent of chiral discrimination. Subsequently the tablet formulation (Rhofenid-100mg) was administered, at a dose equivalent to 10 mg/kg, to assess the enantiospecific bioavailability of KT enantiomers in the rabbit following the same protocol as followed for the pure KT. In vivo studies revealed that the bioavailability of S-KT is higher than that of the Renantiomer, after oral dosing with both KT-tablet and KT-pure. But the degree of chiral discrimination is more pronounced and more statistically significant in the case KT formulation as reflected by the enantioselective pharmacokinetic data. The observations presented in this article further emphasize the significance of differentiating between enantiomers of chiral drugs when assessing bioavailability and correlating efficiency with drug concentration. The study opens up a new avenue to the design of stereoselective dosage forms.

KEY WORDS
ketoprofen enantiomers; enantiospecific; pharmacokinetic; bioavailability; chiral HPLC


REFERENCES
Adams SS, Breshloff P, Mason CG: Pharmacological difference between the optimal isomers of Ibuprofen: evidence for metabolic inversion of the (-)-isomer. J Pharm Pharmacol 28:256-257, 1976.

Bjorkman S: Determination of the enantiomers of indoprofen in blood plasma by highperformance liquid chromatography after rapid derivatization by means of ethyl chloroformate. J Chromatogr 339:339-346, 1985.

Bjorkman S: Determination of the enantiomers of ketoprofen in blood plasma by ion-pair extraction and high-performance liquid chromatography of leucinamide derivatives. J Chromatogr A 414:465-471, 1987.

Caldwell J: Chiral pharmacology and the regulation of new drugs. Chem Ind 6:176-179, 1995.

Crom WR: Effect of chirality on pharmacokinetics and pharmacodynamics. Am J Hosp Pharm 59:S9-S14, 1992.

Duddu SP, Vakilynejad M, Jamali F, Grant DJW: Stereoselective dissolution of propranolol hydrochloride from hydroxypropyl methylcellulose matrices. Pharm Res 10:1648-1652, 1993.

Evans AM: Enantioselective pharmacodynamics and pharmacokinetics of chiral non-steroidal anti-inflammatory drugs. Eur J Clin Pharmacol 42:237-256, 1992.

Foster RT, Jamali F: High-performance liquid chromatographic assay of ketoprofen enantiomers in human plasma and urine. J Chromatogr 426:388-393, 1987.

Gibaldi M: Compartmental and noncompartmental pharmacokinetics. In Gibaldi M (ed.): Biopharmaceutics and Clinical Pharmacokinetics, Lea and Febiger, Philadelphia, London 1991, pp. 14-23.

Hutt AJ, Caldwell J: The importance of stereochemistry in clinical pharmacokinetics of the 2-arylpropionic acid non-steroidal antinflammatory drugs. Clin Pharmacokinet 9:371-373, 1984.

Hutt AJ, Caldwell J: The metabolic chiral inversion of 2-arylpropionic acids- a novel route with pharmacological consequence. Pharm Pharmacol 35:693-704, 1983.

Jamali F, Mehvar R, Pasutto FM: Enantioselective aspects of drug action and disposition: therapeutic pitfalls. J Pharm Sci 78:695-715, 1989.

Mullangi R, Yao M, Srinivasan NR: Resolution of enantiomers of ketoprofen by HPLC: a review. Biomed Chromatogr 17:423-434, 2003.

Patocka J, Dvorak A: Biomedical aspects of chiral molecules. J Appl Biomed 2:95-100, 2004.

Solinis MA, Cruz YDL, Calco B et al.: Release of salbutamol and ketoprofen enantiomers containing HPMC and cellulose derivatives. Chirality 14:806-813, 2002.

Somogyi A, Bochner F, Foster D: Inside the isomers: the tale of chiral switches. Aust Prescr 27:47-49, 2004.

Strong MS: FDA policy and regulation of stereoisomers: Paradigm shift and the future of safer, more effective drugs. Food Drug Law J 54:463-487, 1999.

Valliappan K, Kannan K, Manavalan R, Muralidharan C: Evaluation of stereoselective dissolution of racemic ketoprofen from formulations containing chiral excipients. Indian J Pharm Sci 65:253-259, 2003.

Valliappan K, Kannan K, Manavalan R, Muralidharan C: Prediction of chiral separation of ketoprofen using experimental design. Indian J Chem 41A:1334-1340, 2002.

Valliappan K: Molecular handedness: Impact on the development of chiral drugs. Indian Drugs 35:446-457, 1998.

Williams KM: Clinical applications of enantiomeric drugs. Aust Prescr 12:22-25, 1989.
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Abdallah MH, Sammour OA, El-Ghamry HA, El-Nahas HM, Barakat W. Development and characterization of controlled release ketoprofen microspheres. J Appl Pharm Sci. 2: 60-67, 2012.

Hosny KM, Ali SM. Novel controlled release oxypentifylline microspheres; Preparation, characterization and in-vivo evaluation. Afr J Pharm Pharmacol. 6: 2039-2048, 2012.

Hosny KM, Ali SM. Controlled release ammonio methacrylate copolymer-based microspheres of oxypentifylline. Int J Drug Del. 3: 734-742, 2011.

Sarfraz A, Sarfraz M, Ahmad M. Development and validation of a bioanalytical method for direct extraction of diclofenac potassium from spiked plasma. Tropic J Pharm Res. 10: 663-669, 2011.

Ivanov IT, Tsokeva Z. Effect of chirality on PVP/drug interaction within binary physical mixtures of Ibuprofen, Ketoprofen, and Naproxen: A DSC Study. Chirality. 21: 719-727, 2009.

Sivakumar T, Manavalan R, Valliappan K. Global optimization using Derringer's desirability function: Enantioselective determination of ketoprofen in formulations and in biological matrices. Acta Chromatogr. 19: 29-47, 2007.

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