Stereoselective Pharmacokinetics

  • Alberto Tajana
Part of the NATO ASI Series book series (NSSA, volume 221)


Many drugs are marketed as racemates, i.e. equimolar mixtures of molecules with the same molecular formula (isomers) that differ only in the arrangement of their atoms in space (stereoisomers) and are related as two non-superimposable mirror images (enantiomers).


High Performance Liquid Chromatography Chiral Center Chiral Stationary Phase Tiaprofenic Acid Pure Enantiomer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abas A, Meffin PJ., 1987. Enantioselective disposition of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs. IV. Ketoprofen disposition. J. Pharmacol. Exp. Ther. 240: 637.PubMedGoogle Scholar
  2. Aberg G., 1972. Toxicological and local anaesthetic effects of optically active isomers of two local anaesthetic compounds. Acta Pharmacol. Toxicol. 31: 273.Google Scholar
  3. Akerman B, Persson H, Tegner C., 1967. Local anesthetic pmperties of the optically active isomers of prilocaine (Citanest). Acta Pharmacol. Toxicol. 25: 233.Google Scholar
  4. Ames MM, Frank SK., 1982. Stereochemical aspects of para-chloramphetamine metabolism. Biochem. Pharmacol. 31: 5.PubMedCrossRefGoogle Scholar
  5. Aps C, Reynolds F., 1978. An intradermal study of the local anaesthetic and vascular effects of the isomers of bupivacaine. Br. J. Clin. Phartnacol. 6: 63.Google Scholar
  6. Armstrong DW., 1987. Optical isomer separation by liquid chromatography. Anal. Chem. 59: 84A.PubMedCrossRefGoogle Scholar
  7. Armstrong DW, Ward TJ, Armstrong RD, Beesley TE., 1986. Separation of drug stereoisomers by the deformation of 13-cyclodexttin inclusion complexes. Science. 232: 1132.PubMedCrossRefGoogle Scholar
  8. Bai SA, Walle UK, Wilson MJ, Walle T., 1983. Stereoselective binding of the enantiomer of propranolol to plasma and extravascular binding sites in the dog. Drug Metab. Dispos. 11: 394.Google Scholar
  9. Banfield C, O’Reilly R, Chan E, Rowland M., 1983. Phenylbutazone-warfarin interaction in man: Further stereochemical and metabolic considerations. Br. J. Clin. Pharmacol. 16: 669.PubMedGoogle Scholar
  10. Bjorkman S., 1985. Stereoselective disposition of indoprofen in surgical patients. Br. J. Clin. Pharmacol. 20: 463.PubMedGoogle Scholar
  11. Block AJ, Merrill D, Smith ER., 1988. Stereoselectivity of tocainide pharmacodynamics in vivo and in vitro. J. Cardiovasc. Pharmacol. 11: 216.PubMedGoogle Scholar
  12. Borgstrom L, Nyberg L, Jonsson S et al., 1989. Pharmacokinetic evaluation in man of terbutaline given as separate enantiomers and as the racemate. Br. J. Clin. Pharmacol. 27: 49.PubMedGoogle Scholar
  13. Boyd RA, Chin SK, Don-Pedro O et al., 1989. The pharmacokinetics of the enantiomers of atenolol. Clin. Pharmacol. Ther. 454: 403.CrossRefGoogle Scholar
  14. Branch RA, Nies AS, Shand DG., 1973. The disposition of propranolol. VII. Drug Metab. Dispos. 1: 687.Google Scholar
  15. Breckenridge AM, Orme MLE., 1972. The plasma half-lives and the pharmacological effect of the enantiomers of warfarin in rats. Life Sci. 11: 337.CrossRefGoogle Scholar
  16. Cahn RS, Ingold C, Prelog V., 1966. Specification of molecular chirality. Angev. Chem. Intern. Ed. Engl. 5: 385.CrossRefGoogle Scholar
  17. Caldwell J, Marsh MV., 1983. Interrelationships between xenobiotic metabolism and lipid biosynthesis. Biochem. Pharmacol. 32: 1667.PubMedCrossRefGoogle Scholar
  18. Caldwell J, Hutt AJ, Fournel-Gigleux S., 1988. The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences. Biochem. Pharmacol. 37: 105.PubMedCrossRefGoogle Scholar
  19. Cartwright AC., 1990. Stereochemistry and safety, efficacy and quality issues: genesis of new regulations. Drug Informat. J. 24: 115.CrossRefGoogle Scholar
  20. Christ DD, Walle T., 1985. Stereoselective sulfate conjugation of 4hydroxypropranolol in vitro by different species. Drug Metab. Dispos. 13: 380.Google Scholar
  21. Coltart DJ, Shand DG., 1970. Plasma propranolol levels in the quantitative measurement of adrenergic blockade in man. Brit. Med. J. 3: 731.PubMedCrossRefGoogle Scholar
  22. Cook CE, Seltzman TB, Tallent CR et al., 1987. Pharmacokinetics of pentobarbital enantiomers as determined by enantioselective radioimmunoassay after administration of racemate to humans and rabbits. J. Pharmacol. Exp. Ther. 241: 779.PubMedGoogle Scholar
  23. Crooks PA, Godin CS., 1988. N-Methylation of nicotine enantiomers by human liver cytosol. J. Pharm. Pharmacol. 40: 153.PubMedCrossRefGoogle Scholar
  24. Dalgliesh CE., 1952. The optical resolution of aromatic amino-acids on the paper chromatograms. J. Chem. Soc. 137: 3940.CrossRefGoogle Scholar
  25. Day RO, Williams KM, Graham GG et al., 1989. Stereoselective disposition of ibuprofen enantiomers in synovial fluid. Clin. Pharmacol. Ther. 435: 480.Google Scholar
  26. Echizen H, Brecht T, Niedergesaess S et al., 1985. The effect of dextro, levo and racemic verapamil on atrioventricular conduction in man. Am. Heart J. 109: 210.PubMedCrossRefGoogle Scholar
  27. Edgar B, Heggelund A, Johansson L et al., 1984. The pharmacokinetics of R- and S-tocainide in healthy subjects. Br. J. Clin. Pharmacol. 16: 216 P.Google Scholar
  28. Eichelbaum M, Mikus G, Vogelgesang B., 1984. Pharmacokinetics of and verapamil after intravenous administration. Br. J. Clin. Pharmacol. 17: 453.PubMedGoogle Scholar
  29. Eichelbaum M., 1988. Pharmacokinetic and pharmacodynamic consequences of stereoselective drug metabolism in man. Biochem. Pharmacol. 37: 93PubMedCrossRefGoogle Scholar
  30. Evans AM, Nation RL, Sansom LN et al., 1989. Stereoselective plasma protein binding of ibuprofen enantiomers. Eur. J. Clin. Pharmacol. 36: 283.PubMedCrossRefGoogle Scholar
  31. Foster RT, Jamali F., 1988a. Stereoselective pharmacokinetics of ketoprofen in the rat. Influence of route of administration. Drug Metab. Dispos. 16: 623Google Scholar
  32. Foster RT, Jamali F, Russell AS, AlbaIla SR., 1988b. Pharmacokinetics of ketoprofen enantiomers in healthy subjects following single and multiple doses. J. Pharm. Sci. 77: 70.PubMedCrossRefGoogle Scholar
  33. Foster RT, Jamali F, Russell AS, Alballa SR., 1988c. Pharmacokinetics of ketoprofen enantiomers in young and elderly arthritic patients following single and multiple doses. J. Pharm. Sci. 77: 191.PubMedCrossRefGoogle Scholar
  34. Giacomini KM, Nelson WL, Pershe RA et al., 1986. In vivo interaction of the enantiomers of disopyramide in human subjects. J. Pharmacokinet. Biopharm. 14: 335.PubMedCrossRefGoogle Scholar
  35. Hague D, Smith RL., 1988. Enigmatic properties of thalidomide; an example of a stable racemic compound. Br. J. Clin. Pharmacol. 26: 632 P.Google Scholar
  36. Hendel J, Brodthagen H., 1984. Entero-hepatic cycling of methotrexate estimated by the use of the D-isomer as a reference marker. Eur. J. Clin. Pharmacol. 26: 103.PubMedCrossRefGoogle Scholar
  37. Hsyu P-H, Giacomini KM., 1985. Stereoselective renal clearance of pindolol in humans. J. Clin. Invest. 76: 1720.PubMedCrossRefGoogle Scholar
  38. Hutt AJ, Caldwell J., 1983. The metabolic chiral inversion of 2-arylpropionic acids. A novel route with pharmacological consequences. J. Pharm. Pharmacol. 35: 693.PubMedCrossRefGoogle Scholar
  39. Jamali F., 1988. Pharmacokinetics of enantiomers of chiral non-steroidal anti-inflammatory drugs. Eur. J. Drug Metab. Pharmacolcinet. 13: 1.CrossRefGoogle Scholar
  40. Jamali F, Mehvar R, Lemko C, Eradiri O., 1988a. Application of a stereospecific high-performance liquid chromatography assay to a pharmacoldnetic study of etodolac enantiomers in humans. J. Pharm. Sci. 77: 963.PubMedCrossRefGoogle Scholar
  41. Jamali F, Singh NN, Pasutto FM et al., 1988b. Pharmacoldnetics of ibuprofen enantiomers in human following oral administration of tablets with different absorption rates. Pharmacol. Res. 5: 40.CrossRefGoogle Scholar
  42. Jamali F, Mehvar R, Pasutto FM., 1989. Enantioselective Aspects of Drug Action and Disposition: Therapeutic Pitfalls. J. Pharm. Sci. 78: 695.PubMedCrossRefGoogle Scholar
  43. Jenner P, Testa B., 1973. The Influence of Stereochemical Factors in Drug Disposition. Drug Metab. Rev. 2: 117.Google Scholar
  44. Johnson DM, Reuter A, Collins JM, Thompson GF., 1979. Enantdomeric purity of naproxen by liquid chromatographic analysis of its diastereomeric octyl esters. J. Pharm. Sci. 68: 112.PubMedCrossRefGoogle Scholar
  45. Kamerling JP, Duran M, Gerwig GJ et al., 1981. Determination of the absolute configuration of some biologically important urinary 2-hydroxydicarboxylic acids by capillary gas-liquid chromatography. J. Chromatogr. 222: 276.PubMedCrossRefGoogle Scholar
  46. Karnes HT, Sarkar MA., 1987. Enantiomeric resolution of drug compounds by liquid chromathography. Pharmaceut. Res. 4: 285.CrossRefGoogle Scholar
  47. Kawashima R, Levy A, Spector S., 1976. Stereospecific radioimmunoassay for propranolol isomers. J. Pharmacol. Exp. Ther. 196: 517.PubMedGoogle Scholar
  48. Kunlcumian CS., 1990. Regulatory considerations concerning stereioisomers in drug products. Drug Informat. J. 24: 125.CrossRefGoogle Scholar
  49. Le Corre P, Gibassier D, Sado P, Le Verge R., 1988. Stereoselective metabolism and pharmacokinetics of disopyramide enantiomers in humans. Drug Metab. Disp. 16: 858.Google Scholar
  50. Lee EJD, Williams K, Day R. et al., 1985. Stereoselective disposition of ibuprofen enantiomers in man. Brit. J. Clin. Pharmacol. 19: 669.Google Scholar
  51. Lee EJD, Williams KM., 1990. Chirality. Clinical Pharmacokinetic and Pharmacodynatnic Considerations. Clin. Pharmacoldnet. 18: 339.CrossRefGoogle Scholar
  52. Lennard MS, Tucker GT, Silas JH et al., 1983. Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolisers. Clin. Phartnacol. Ther. 34: 732.CrossRefGoogle Scholar
  53. Lepage J, Lindner W, Davies G. Karger B., 1979. Resolution of the optical isomers of dancyl amino acids by reversed phase liquid chromatography with optically active metal chelate additives. Anal. Chem. 51: 433.CrossRefGoogle Scholar
  54. Lewis RJ, Trager WF, Chan KK et al., 1974. Warfarin: Stereochemical aspects of its metabolism and the interaction with phenylbutazone. J. Clin. Invest. 53: 1607.PubMedCrossRefGoogle Scholar
  55. Lima JJ, Boudoulas H, Shields B., 1985. Stereoselective pharmacokinetics of disopyramide enantiomers in man. Drug Metab. Dispos. 13: 572.Google Scholar
  56. Luduena FP., 1969. Duration of local anesthesia. Ann. Rev. Pharmacol. 9: 503.PubMedCrossRefGoogle Scholar
  57. Mikus G, Kroemer HK, Klotz U Eichelbaum M., 1988. Stereochemical considerations of the cimetidine-verapamil interaction. Clin. Pharmacol. Ther. 43: 134Google Scholar
  58. Nakazawa H, Yoneda H., 1978. Chromatographic study of optical resolution. II. Separation of optically active cobalt (III) complexes using potassium antimony d-tartrate as eluent. J. Chromatogr. 160: 89.CrossRefGoogle Scholar
  59. Nies AS, Evans GR, Shand DG., 1973. Regional hemodynamic effects of adrenergic blockade with propranolol in the unanesthetized primate. Amer. Heart J. 85: 97.PubMedCrossRefGoogle Scholar
  60. Notterman DA, Drayer DE, Metakis L, Reidenberg MM., 1986. Stereoselective renal tubular secretion of quinidine and quinine. Clin. Pharmacol. Ther. 40: 511.PubMedCrossRefGoogle Scholar
  61. O’Reilly RA, Trager WF, Motley CH, Howald W., 1980. Stereoselective interaction of phenylbutazone with (12C/13C) warfarin pseudoracemates in man. J. Clin. Invest. 65: 746.PubMedCrossRefGoogle Scholar
  62. Ofori-Adjei D, Ericsson O, Lindstrom B et al., 1986. Enantioselective analysis of chloroquine and desethylchloroquine after oral administration of racemic chloroquine. Ther. Drug Monit. 8: 457.PubMedCrossRefGoogle Scholar
  63. Olivieri R, Fascetti E, Angelini L, Degen L., 1981. Enzymic conversion of N- carbamoyl-D-amino acids to D-amino acids. Biotechnol. Bioeng. 23: 2173.CrossRefGoogle Scholar
  64. Otton SV, Lennard MS, Tucker GT, Woods HF., 1989. Cumene hydroperoxidesupported oxidation of propranolol enantiomers by human liver microsomes. Abstractc No. PP 02.66. IV World Conference on Clinical Pharmacology, Mannheim-Heidelberg. Eur. J. Clin. Pharmacol. 36 (Suppl.).Google Scholar
  65. Pfeiffer CC., 1956. Optical isomerism and pharmacological action, a generalization. Science 124, 29.PubMedCrossRefGoogle Scholar
  66. Ruelius HW, Tio CO, Knowles JA et al., 1979. Diastereoisomeric glucoronides of oxazepam. Isolation and stereoselective enzymic hydrolysis. Drug Metab. Dispos. 7: 40.Google Scholar
  67. Sallustio BC, Meffin PJ, Knights KM., 1988. The stereospecific incorporation of fenoprofen into rat hepatocyte and adipocyte triacylglycerols. Biochem. Pharmacol. 37: 1919.PubMedCrossRefGoogle Scholar
  68. Schilsky RL, Choi KE, Vokes EE et al., 1989. Clinical pharmacology of the stereoisomers of leucovorin during repeated oral dosing. Cancer. 63: 1018.PubMedCrossRefGoogle Scholar
  69. Sedman AJ,Ga1 J., 1983. Resolution of the enantiomers of propranolol and other ßadrenergic antagonists by high-performance liquid chromatography. J. Chromatogr. 278: 199.CrossRefGoogle Scholar
  70. Sheldon RA., 1990. The industrial synthesis of pure enantiomers. Drug Inform. J. 24: 129.CrossRefGoogle Scholar
  71. Simmonds RG, Woodage TJ, Duff SM, Green JN., 1980. Stereospecific inversion of (R) benoxaprofen in rat and man Eur. J. Drug Metab. Pharmacokinet. 5: 169.PubMedCrossRefGoogle Scholar
  72. Simonyi M, Fitos I, Visy J., 1986. Chirality of bioactive agents in protein binding storage and transport processes. TIPS 7: 112.Google Scholar
  73. Simonyi M, Gal J and Testa B., 1989. Signs of the times: the need for a stereo-chemically informative generic name system. TIPS 10: 349.Google Scholar
  74. Sisenwine SF, Tio CO, Knowles JA et al., 1982. Species-related differences in the stereoselective glucuronidation of oxazepam. Drug Metab. Dispos. 10: 605.Google Scholar
  75. Smith RL, Caldwell J., 1988. Racemates: towards a New Year solution? TIPS 9: 75.Google Scholar
  76. Takahashi H, Kanno S, Ogata H et al., 1988. Determination of propranolol enantiomers in human plasma and urine and rat tissues using chiral stationary-phase liquid chromatography. J. Pharm. Sci. 77: 993.PubMedCrossRefGoogle Scholar
  77. Tamai I, Ling H-Y, Timbul S-M et al., 1988. Stereospecific absorption and degradation of cephalexin. J. Pharm. Pharmacol. 40: 320.PubMedCrossRefGoogle Scholar
  78. Testa B., 1989. Mechanism of chiral recognition in xenobiotic metabolism and drug-receptor interactions. Chirality. 1: 7.PubMedCrossRefGoogle Scholar
  79. Thijssen HHW, Baars LGM, Drittij-Reijnders MJ., 1985. Stereoselective aspects in the pharmacolcinetics and pharmacodynamics of acenocoumarol and its amino and acetamido derivatives in the rat. Drug Metab. Dispos. 13: 593.Google Scholar
  80. Thijssen HHW, Baars LGM., 1987. The biliary excretion of acenocoumarol in the rat: Stereochemical aspects. J. Pharm. Pharmacol. 39: 655.PubMedCrossRefGoogle Scholar
  81. Tocco DJ, Hooke KF, Deluna FA, Duncan AEW., 1976. Stereospecific binding of timolol, a 13-adrenergic blocldng agent. Drug Metab. Dispos. 4: 323.Google Scholar
  82. Thomson AH, Murdoch G, Pottage A et al., 1986. The pharmacokinetics of R- and S-tocainide in patients with acute ventricular arrhythmias. Brit. J. Clin. Pharrnacol. 21: 149.Google Scholar
  83. Toon S, Low LK, Gibaldi M et al., 1986. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin. Pharmacol. Ther. 39: 15.PubMedCrossRefGoogle Scholar
  84. Toon S, Hopldns KJ, Garstang FM, Rowland M., 1987. Comparative effects of ranitidine and cimetidine on the pharmacoldnetics and pharmacodynamics of warfarin in man. Eur. J. Clin. Pharmacol. 32: 165.PubMedCrossRefGoogle Scholar
  85. Tucker GT, Lennard MS., 1990. Enantiomer specific pharmacokinetics. Pharm. Ther. 45: 309.CrossRefGoogle Scholar
  86. Vogelgesang B, Echizen H, Schmidt E, Eichelbaum M., 1984. Stereoselective first-pass metabolism of highly cleared drugs: studies of the bioavailability of L- and D-verapamil examined with a stable isotope technique. Br. J. Clin. Pharmacol. 18: 733.PubMedGoogle Scholar
  87. Wade DN, Mearrick PT, Morris JL., 1973. Active transport of L-dopa in the intestine. Nature. 242: 463.PubMedCrossRefGoogle Scholar
  88. Wainer IW, Barkan SA, Schill G., 1986. oci-Acid glycoprotein chiral stationary phase. HPLC application to the resolution of enantiomeric drugs. LC/GC Mag. 5: 422.Google Scholar
  89. Walle T, Walle UK., 1979. Stereoselective bioavailability of (±) propranolol in the dog. A GC-MS study using a stable isotope technique. Res. Commun. Chem. Pat. Pharmacol. 23: 453.Google Scholar
  90. Walle T, Walle UK, Wilson MJ et al., 1984. Stereoselective ring oxidation of propranolol in man. Br. J. Clin. Pharmacol. 18: 741.PubMedGoogle Scholar
  91. Walle T, Webb JG, Bagwell EE et al., 1988. Stereoselective delivery and actions of beta receptor antagonists. Biochem. Pharmacol. 37: 115.PubMedCrossRefGoogle Scholar
  92. Ward S, Branch RA, Walle T, Walle UK., 1986. Cosegregation of propranolol metabolism with debrisoquine and mephenytoyn polymorphism. Pharmacologist 28: 137.Google Scholar
  93. Ward SA, Walle T, Walle UK et al., 1989. Propranolol’s metabolism is determined by both mephenytoin and debrisoquine hydroxylase activities. Clin. Pharmacol. Ther. 45: 72.PubMedCrossRefGoogle Scholar
  94. Webb JG, Street JA, Bagwell EE et al., 1988. Stereoselective secretion of atenolol from PC12 cells. J. Pharmacol. Exp. Ther. 247: 958.PubMedGoogle Scholar
  95. Wilkinson GR, Shand DG., 1975. A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther. 18: 377.PubMedGoogle Scholar
  96. Williams K, Day R, Knihinicki R, Duffield A., 1986. The stereoselective uptake of ibuprofen enantiomers into adipose tissue. Biochem. Pharmacol. 35: 3403.PubMedCrossRefGoogle Scholar
  97. Yacobi A, Levy G., 1974. Pharmacokinetics of the warfarin enantiomers in rats. J. Pharmacokinet. Biopharm. 23: 239.CrossRefGoogle Scholar
  98. Yamaguchi T, Nakamura Y., 1987. Stereoselective metabolism of 2phenylproprionic acid in rat. II. Studies on the organ responsible for the optical isomerization of 2- phenylpropionic acid in rat in vivo. Drug Metab. Dispos. 15: 535.Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Alberto Tajana
    • 1
  1. 1.Department of PharmacokineticsRecordati S.p.A.MilanoItaly

Personalised recommendations