Implications of Stereoselectivity in Clinical Pharmacokinetics

  • M. Eichelbaum
  • A. S. Gross
Part of the NATO ASI Series book series (NSSA, volume 221)

Abstract

Approximately 50% of all drugs in therapeutic use have a chiral center and hence exhibit stereoisomerism. Chiral drugs derived from natural sources are stereochemical pure due to the stereospecificity of biological synthesis. By contrast, most of the drugs with a chiral center produced by chemical synthesis are only available as racemates, since chemical synthesis usually leads to a racemate unless stereospecific synthesis is employed [Roth & Kleemann, 1982; Simonyi, 1984].

Keywords

Migraine Warfarin Propranolol Ibuprofen Cimetidine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ariens EJ., 1984. Stereochemistry, a basis for sophisticated nonsense in pharmacolanetics and clinical pharmacology. Eur J Clin Pharmacol 26: 663.PubMedCrossRefGoogle Scholar
  2. 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
  3. Bayer R, Kaufmann R, Mannhold R., 1975. Inotropic and electrophysiological actions of verapamil and D-600 in mammalian myocardium. II. Pattern of inotropic effects of the optical isomers. Naunyn Schmiedebergs Arch Pharmacol 290: 69.PubMedCrossRefGoogle Scholar
  4. Block AJ, Merrill D, Smith ER., 1988. Stereoselectivity of tocainide pharmacodynamies in vivo and in vitro. J Cardiovasc Pharmacol 11: 216.PubMedGoogle Scholar
  5. Bopp RJ, Nash JF, Ridolfo AS, Shepard ER., 1979. Stereoselective inversion of (R)-(-)-benoxaprofen to the (S)-(+)-enantiomer in humans. Drug Metab Dispos 7: 356.PubMedGoogle Scholar
  6. Caldwell J, Hutt M, Fournel-Gigleux S., 1988. The metabolic chiral inversion and dispositional enantioselectivity of the 2-aryl propionic acids and their biological consequences. Biochem Pharmacol 37: 105.PubMedCrossRefGoogle Scholar
  7. Choonara IA, Cholerton S, Haynes BP, Breckenridge AM, Park BK., 1986. Stereoselective interaction between the R enantiomer of warfarin and cimetidine. Br J Clin Pharmacol 21: 272.Google Scholar
  8. Diekmann H, Garbe A, Steiner K, Bühring KU, Faro HP, Nowak H., 1979. Disposition of thioxaprofene: kinetics of the stereoisomers. Naunyn Schmiedeberg’s Arch Pharmacol 307 (Supp): R3.Google Scholar
  9. Drayer DE., 1986. Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview. Clin Pharmacol Ther 40: 125.PubMedCrossRefGoogle Scholar
  10. Drayer DE., 1988. Problems in therapeutic drug monitoring: the dilemma of enantiomeric drugs in man. Ther Drug Mon 10: 1.Google Scholar
  11. Echizen H, Manz M, Eichelbaum M., 1988. Electrophysiologic effects of dextroand levo-verapamil on sinus node and AV node function in humans. J Cardiovasc Pharmacol 12: 543.PubMedCrossRefGoogle Scholar
  12. Echizen H, Vogelgesang B, Eichelbaum M., 1985. Effects of d,l-verapamil on atrioventricular conduction in relation to its stereoselective first-pass metabolism. Clin Pharmacol Ther. 41: 71.CrossRefGoogle Scholar
  13. Eichelbaum M., 1988. Pharmacokinetic and pharmacodynamic consequences of stereoselective drug metabolism in man. Biochem Pharmacol 37: 93.PubMedCrossRefGoogle Scholar
  14. Eichelbaum M, Mikus G, Vogelgesang B., 1984. Pharmacokinetics of (+), (-) and (±) verapamil after intravenous administration. Br J Clin Pharmacol 17: 453.PubMedGoogle Scholar
  15. Eichelbaum M, Birkel P, Grube E, Gütgemann U, Somogyi A., 1980. Effects of verapamil on P-R intervals in relation to verapamil plasma levels following single I.V. and oral administration and drug chronic treatment. Klin Wochenschr 58: 919.PubMedCrossRefGoogle Scholar
  16. Ferry DR, Glossmann H, Kaumann AJ., 1985. Relationship between the stereoselective negative inotropic effects of verapamil enantiomers and their binding to putative calcium channels in human hearts. Br J Pharmacol 84: 811.PubMedGoogle Scholar
  17. Heyma P, Larkins RG, Higgonbotham L, Ng KW., 1980. D-Propranolol and DLpropranolol both decrease conversion of L-thyroxine to L-triiodothyronine. Br Med J. page 24.Google Scholar
  18. Hill RJ, Duff HJ, Sheldon RS., 1988. Determinants of stereospecific binding of type I antiarrhythmic drugs to cardiac sodium channels. Mol Pharmacol 34: 659.PubMedGoogle Scholar
  19. 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
  20. Jaillon P, Heckle J, Weissenburger J, Cheymol G., 1980. Cardiac electrophysiologic properties of dl-propranolol, d-propranolol,1-propranolol and dl-pindolol in anesthetized dogs. J Pharmacol Exp Ther 212: 347.PubMedGoogle Scholar
  21. Kaiser DG, Vangiessen GJ, Reischer RJ, Wechter WJ., 1976. Isomeric inversion of ibuprofen (R)-enantiomer in humans. J Pharm Sci 65: 269.PubMedCrossRefGoogle Scholar
  22. Knights KM, Drew R, Meffin PJ., 1988. Enantiospecific formation of fenoprofen coenzyme A thioester in vitro. Biochem Pharmacol 37: 3539.PubMedCrossRefGoogle Scholar
  23. Kroemer HK, Funck-Brentano C, Silberstein DJ et al., 1989. Stereoselective disposition and pharmacologic activity of propafenone enantiomers. Circulation 79: 1068.PubMedCrossRefGoogle Scholar
  24. Lee EJD, Williams K, Day R, Graham G, Champion D., 1985. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol 19: 669.PubMedGoogle Scholar
  25. Lehmann FPA, Rodrigues de Miranda JF, Ariens EJ., 1976. Stereoselectivity and affinity in molecular pharmacology. Progress in Drug Research 20: 101.PubMedGoogle Scholar
  26. Lewis RJ, Trager WF, Chan KK et al., 1974. Warfarin: Stereochernical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest 53: 1607.PubMedCrossRefGoogle Scholar
  27. Lie-A-Huen L, van den Alcker J, den Hertog A, Meijer DKF., 1989. The action of flecainide acetate and its enantiomers on mammalian non-myelinated nerve fibres. Pharmaceut Weekbl [Sci] 11: 92.CrossRefGoogle Scholar
  28. Nakamura Y, Yamaguchi T., 1987. Stereoselective metabolism of 2-phenylpropionic acid in rat. Drug Metab Dispos 15: 529.PubMedGoogle Scholar
  29. Nawrath H, Blei I, Gegner R, Ludwig C, Zong X., 1981. No stereospecific effects of the optical isomers of verapamil and D-600 on the heart. In: “Calcium antagonism in cardiovascular therapy: experience with veraparnil” (Zanchetti A, Krilder DM eds.), page 52. Amsterdam, Excerpta Medica.Google Scholar
  30. O’Reilly RA, Trager WF, Motley CH, Howald W.1980. Stereoselective interaction [12c/13 of phenylbutazone with C] warfarin pseudoracemates in man. J Clin Invest 65: 746.PubMedCrossRefGoogle Scholar
  31. O’Reilly RA., 1976. The stereoselective interaction of warfarin and metronidazole in man. New Engl J Med 295: 354.PubMedCrossRefGoogle Scholar
  32. O’Reilly RA., 1980. Stereoselective interaction of trimethoprim-sulfamethoxazole with the separated enantiomorphs of racemic warfarin in man. New Engl J Med 302: 33.PubMedCrossRefGoogle Scholar
  33. O’Reilly RA. Ticrynafen-racemic warfarin interaction: hepatotoxic or stereoselective? Clin Pharmacol Ther 32: 356.Google Scholar
  34. Powell JR, Ambre JJ, Ruo TI., 1988. The efficacy and toxicity of drug stereoisomers. In: “Drug Stereochemistry” ( Wainer IW and Drayer DE, eds.), page 245. Marcell Dekker Inc., New York.Google Scholar
  35. Roth HJ, Kleemann A., 1982. “Arzneistoffsynthese”, pages 16–20. Georg Thieme Verlag, Stuttgart.Google Scholar
  36. Rubin A, Knadler MP, Ho PPK, Bechtol LD, Wolen RL., 1985. Stereoselective inversion of (R)-fenoprofen to (S)-fenoprofen in humans. J Pharm Sci 74: 82.PubMedCrossRefGoogle Scholar
  37. Ruffolo RR, Messick K., 1985. Effects of dopamine, (±)-dobutamine and the (+)- and (-)-enantiomers of dobutamine on cardiac function in pithed rats. J Pharmacol Exp Ther. 235: 558.PubMedGoogle Scholar
  38. Satoh K, Yanagisawa T, Taira N., 1980. Coronary vasodilator and cardiac effects of optical isomers of verapamil in the dog. J Cardiovasc Pharmacol 2: 309.PubMedCrossRefGoogle Scholar
  39. 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
  40. Simonyi M., 1984. On chiral drug action. In “Medicinal Research Reviews”, Vol.4, page 359. John Wiley & Sons, Inc, New York.Google Scholar
  41. Stensrud P, Sjaastad O., 1976. Short-term clinical trial of propranolol in racemic form (Inderal), d-propranolol and placebo in migraine. Acta Neurol Scandinav 53: 229.CrossRefGoogle Scholar
  42. Toon S, Hopkins KJ, Garstang FM, Diquet B, Gill TS, Rowland M., 1986. The warfarin-cimetidine interaction: stereochemical considerations. Br J Clin Pharmacol 21: 245.PubMedGoogle Scholar
  43. Toon S, Hopkins KJ, Garstang FM, Aarons L, Sedman A, Rowland M., 1987. Enoxacin-warfarin interaction: Pharmacokinetic and stereochemical aspects. Clin Pharmacol Ther 42: 33.PubMedCrossRefGoogle Scholar
  44. Toon S, Low LK, Gibaldi M et al., 1986. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Phannacol Ther 39: 15.CrossRefGoogle Scholar
  45. Tucker GT, Lennard MS., 1990. Enantiomer specific pharmacokinetics. Phannac Ther 45: 309.CrossRefGoogle Scholar
  46. Uprichard ACG, Allen JD, Harron DWG., 1988. Effects of tocainide enantiomers on experimental arrhythmias produced by programmed electrical stimulation. J Cardiovasc Pharmacol. 11: 235.PubMedGoogle Scholar
  47. Vogelgesang B, Echizen H, Schmidt E, Eichelbaum M., 1984. Stereoselective first-pass metabolism of highly cleared drugs: studies of the bioavailability of 1- and dverapamil examined with a stable isotope technique. Br J Clin Pharmacol 18: 733.PubMedGoogle Scholar
  48. Williams K, Lee E., 1985. Importance of drug enantiomers in clinical pharmacology. Drugs 30: 333.PubMedCrossRefGoogle Scholar
  49. Yamaguchi T, Nakamura Y., 1987. Stereoselective metabolism of 2-phenylpropionic acid in rat. Drug Metab Dispos. 15: 535.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • M. Eichelbaum
    • 1
  • A. S. Gross
    • 1
  1. 1.Fischer-Bosch-Institut für Klinische PharmakologieStuttgartFederal Republic of Germany

Personalised recommendations