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. 1988 Dec;26(6):771–780. doi: 10.1111/j.1365-2125.1988.tb05318.x

Stereoselective drug disposition: potential for misinterpretation of drug disposition data.

A M Evans 1, R L Nation 1, L N Sansom 1, F Bochner 1, A A Somogyi 1
PMCID: PMC1386594  PMID: 3242583

Abstract

1. Although it is well recognised that the enantiomers of a chiral drug may possess different pharmacokinetic and pharmacodynamic properties, many studies dealing with chiral drugs which are administered as their racemates rely on non-stereoselective analytical techniques. 2. We present a theoretical analysis to illustrate the potential which exists for misinterpretation of drug disposition and plasma drug concentration-effect data generated for a racemic drug using a non-stereoselective assay. 3. It was shown that the use of such an analytical method can lead to the collection of data which may be both quantitatively and qualitatively inaccurate with respect to the individual enantiomers. For example, the clearance of the unresolved drug may indicate concentration- and time-dependence even though this pharmacokinetic process is concentration- and time-independent for each of the enantiomers. 4. The problems discussed emphasise the need to consider stereoselectivity in clinical pharmacological studies involving racemic drugs.

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Selected References

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  1. Aarons L., Grennan D. M., Rajapakse C., Brinkley J., Siddiqui M., Taylor L., Higham C. Anti-inflammatory (ibuprofen) drug therapy in rheumatoid arthritis--rate of response and lack of time dependency of plasma pharmacokinetics. Br J Clin Pharmacol. 1983 Mar;15(3):387–388. doi: 10.1111/j.1365-2125.1983.tb01517.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adams S. S., Bresloff P., Mason C. G. Pharmacological differences between the optical isomers of ibuprofen: evidence for metabolic inversion of the (-)-isomer. J Pharm Pharmacol. 1976 Mar;28(3):256–257. doi: 10.1111/j.2042-7158.1976.tb04144.x. [DOI] [PubMed] [Google Scholar]
  3. Albert K. S., Gillespie W. R., Wagner J. G., Pau A., Lockwood G. F. Effects of age on the clinical pharmacokinetics of ibuprofen. Am J Med. 1984 Jul 13;77(1A):47–50. doi: 10.1016/s0002-9343(84)80018-2. [DOI] [PubMed] [Google Scholar]
  4. Ariëns E. J. Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur J Clin Pharmacol. 1984;26(6):663–668. doi: 10.1007/BF00541922. [DOI] [PubMed] [Google Scholar]
  5. Ariëns E. J., Wuis E. W. Bias in pharmacokinetics and clinical pharmacology. Clin Pharmacol Ther. 1987 Oct;42(4):361–363. doi: 10.1038/clpt.1987.163. [DOI] [PubMed] [Google Scholar]
  6. Balant L., Muir K., Dayer P., Gorgia A., Eberlin J. L., Estreicher J., Fabre J. Simultaneous tubular excretion and reabsorption of pindolol in man. Eur J Clin Pharmacol. 1981;21(1):65–72. doi: 10.1007/BF00609590. [DOI] [PubMed] [Google Scholar]
  7. Byrnes E. W., McMaster P. D., Smith E. R., Blair M. R., Boyes R. N., Duce B. R., Feldman H. S., Kronberg G. H., Takman B. H., Tenthorey P. A. New antiarrhythmic agents. 1. Primary alpha-amino anilides. J Med Chem. 1979 Oct;22(10):1171–1176. doi: 10.1021/jm00196a005. [DOI] [PubMed] [Google Scholar]
  8. Cunningham J. L., Shen D. D., Shudo I., Azarnoff D. L. The effects of urine pH and plasma protein binding on the renal clearance of disopyramide. Clin Pharmacokinet. 1977 Sep-Oct;2(5):373–383. doi: 10.2165/00003088-197702050-00004. [DOI] [PubMed] [Google Scholar]
  9. Drayer D. E. Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview. Clin Pharmacol Ther. 1986 Aug;40(2):125–133. doi: 10.1038/clpt.1986.150. [DOI] [PubMed] [Google Scholar]
  10. Gallo J. M., Gall E. P., Gillespie W. R., Albert K. S., Perrier D. Ibuprofen kinetics in plasma and synovial fluid of arthritic patients. J Clin Pharmacol. 1986 Jan;26(1):65–70. doi: 10.1002/j.1552-4604.1986.tb02905.x. [DOI] [PubMed] [Google Scholar]
  11. Giacomini K. M., Cox B. M., Blaschke T. F. Comparative anticholinergic potencies of R- and S- disopyramide in longitudinal muscle strips from guinea pig ileum. Life Sci. 1980 Sep 29;27(13):1191–1197. doi: 10.1016/0024-3205(80)90471-3. [DOI] [PubMed] [Google Scholar]
  12. Giacomini K. M., Nelson W. L., Pershe R. A., Valdivieso L., Turner-Tamiyasu K., Blaschke T. F. In vivo interaction of the enantiomers of disopyramide in human subjects. J Pharmacokinet Biopharm. 1986 Aug;14(4):335–356. doi: 10.1007/BF01059195. [DOI] [PubMed] [Google Scholar]
  13. Giacomini K. M., Swezey S. E., Turner-Tamiyasu K., Blaschke T. F. The effect of saturable binding to plasma proteins on the pharmacokinetic properties of disopyramide. J Pharmacokinet Biopharm. 1982 Feb;10(1):1–14. doi: 10.1007/BF01059180. [DOI] [PubMed] [Google Scholar]
  14. Grech-Belanger O., Turgeon J., Gilbert M. Stereoselective disposition of mexiletine in man. Br J Clin Pharmacol. 1986 May;21(5):481–487. doi: 10.1111/j.1365-2125.1986.tb02829.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hewick D. S., McEwen J. Plasma half-lives, plasma metabolites and anticoagulant efficacies of the enantiomers of warfarin in man. J Pharm Pharmacol. 1973 Jun;25(6):458–465. doi: 10.1111/j.2042-7158.1973.tb09133.x. [DOI] [PubMed] [Google Scholar]
  16. Ho I. K., Harris R. A. Mechanism of action of barbiturates. Annu Rev Pharmacol Toxicol. 1981;21:83–111. doi: 10.1146/annurev.pa.21.040181.000503. [DOI] [PubMed] [Google Scholar]
  17. Lee E. J., Williams K., Day R., Graham G., Champion D. Stereoselective disposition of ibuprofen enantiomers in man. Br J Clin Pharmacol. 1985 May;19(5):669–674. doi: 10.1111/j.1365-2125.1985.tb02694.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lennard M. S., Tucker G. T., Silas J. H., Freestone S., Ramsay L. E., Woods H. F. Differential stereoselective metabolism of metoprolol in extensive and poor debrisoquin metabolizers. Clin Pharmacol Ther. 1983 Dec;34(6):732–737. doi: 10.1038/clpt.1983.242. [DOI] [PubMed] [Google Scholar]
  19. Lima J. J., Boudoulas H., Shields B. J. Stereoselective pharmacokinetics of disopyramide enantiomers in man. Drug Metab Dispos. 1985 Sep-Oct;13(5):572–577. [PubMed] [Google Scholar]
  20. Lockwood G. F., Albert K. S., Gillespie W. R., Bole G. G., Harkcom T. M., Szpunar G. J., Wagner J. G. Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships. Clin Pharmacol Ther. 1983 Jul;34(1):97–103. doi: 10.1038/clpt.1983.136. [DOI] [PubMed] [Google Scholar]
  21. Lockwood G. F., Albert K. S., Szpunar G. J., Wagner J. G. Pharmacokinetics of ibuprofen in man--III: Plasma protein binding. J Pharmacokinet Biopharm. 1983 Oct;11(5):469–482. doi: 10.1007/BF01062206. [DOI] [PubMed] [Google Scholar]
  22. Meffin P. J., Robert E. W., Winkle R. A., Harapat S., Peters F. A., Harrison D. C. Role of concentration-dependent plasma protein binding in disopyramide disposition. J Pharmacokinet Biopharm. 1979 Feb;7(1):29–46. doi: 10.1007/BF01059439. [DOI] [PubMed] [Google Scholar]
  23. Sedman A. J., Gal J., Mastropaolo W., Johnson P., Maloney J. D., Moyer T. P. Serum tocainide enantiomer concentrations in human subjects. Br J Clin Pharmacol. 1984 Jan;17(1):113–115. doi: 10.1111/j.1365-2125.1984.tb05012.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Thomson A. H., Murdoch G., Pottage A., Kelman A. W., Whiting B., Hillis W. S. The pharmacokinetics of R- and S-tocainide in patients with acute ventricular arrhythmias. Br J Clin Pharmacol. 1986 Feb;21(2):149–154. doi: 10.1111/j.1365-2125.1986.tb05169.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Toon S., Low L. K., Gibaldi M., Trager W. F., O'Reilly R. A., Motley C. H., Goulart D. A. The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther. 1986 Jan;39(1):15–24. doi: 10.1038/clpt.1986.3. [DOI] [PubMed] [Google Scholar]
  26. Vogelgesang B., Echizen H., Schmidt E., Eichelbaum M. 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. 1984 Nov;18(5):733–740. doi: 10.1111/j.1365-2125.1984.tb02536.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wagner J. G., Albert K. S., Szpunar G. J., Lockwood G. F. Pharmacokinetics of ibuprofen in man IV: absorption and disposition. J Pharmacokinet Biopharm. 1984 Aug;12(4):381–399. doi: 10.1007/BF01062664. [DOI] [PubMed] [Google Scholar]
  28. White P. F., Ham J., Way W. L., Trevor A. J. Pharmacology of ketamine isomers in surgical patients. Anesthesiology. 1980 Mar;52(3):231–239. doi: 10.1097/00000542-198003000-00008. [DOI] [PubMed] [Google Scholar]
  29. Williams K., Lee E. Importance of drug enantiomers in clinical pharmacology. Drugs. 1985 Oct;30(4):333–354. doi: 10.2165/00003495-198530040-00003. [DOI] [PubMed] [Google Scholar]
  30. Yacobi A., Levy G. Protein binding of warfarin enantiomers in serum of humans and rats. J Pharmacokinet Biopharm. 1977 Apr;5(2):123–131. doi: 10.1007/BF01066216. [DOI] [PubMed] [Google Scholar]

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