Stereoselectivity in Pharmacokinetics: a General Theory

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 1991 May 1

PMID 1866367

Citations 13

Authors

R H Levy

A V Boddy

Affiliations

Soon will be listed here.

Abstract

Stereoselectivity in pharmacokinetics may be characterized by a measurable difference between enantiomers in a pharmacokinetic parameter. We propose that pharmacokinetic parameters may be classified according to three levels of organization in the body and that the hybrid character of parameters increases with the level of organization that they represent. At the molecular level are intrinsic metabolite formation clearances and fraction of drug unbound in plasma, reflecting the selectivity of an endogenous macromolecule for the enantiomers of a chiral drug molecule. At the organ level, pharmacokinetic parameters represent the combined effects of stereoselectivity in each of their component parameters within an organ. As a result, these parameters are of intermediate hybrid character. Parameters with the highest degree of hybrid character describe the pharmacokinetic behavior of a drug in the whole body. The stereoselectivity associated with each of the component parameters could either amplify or dampen the resultant stereoselectivity in hybrid parameters. The hypothesis that kinetic differences between enantiomers are inversely correlated with the degree of hybrid character was examined for four drugs: warfarin, verapamil, mephenytoin, and propranolol. By classifying pharmacokinetic parameters according to both the level of organization that they characterize and their hybrid nature, it becomes possible to account for stereoselectivity in drug distribution and elimination.

Citing Articles

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References

Walle T, WEBB J, BAGWELL E, Walle U, DANIELL H, Gaffney T . Stereoselective delivery and actions of beta receptor antagonists. Biochem Pharmacol. 1988; 37(1):115-24. DOI: 10.1016/0006-2952(88)90763-0. View

Williams K, Lee E . Importance of drug enantiomers in clinical pharmacology. Drugs. 1985; 30(4):333-54. DOI: 10.2165/00003495-198530040-00003. View

Mehvar R, Jamali F . Pharmacokinetic analysis of the enantiomeric inversion of chiral nonsteroidal antiinflammatory drugs. Pharm Res. 1988; 5(2):76-9. DOI: 10.1023/a:1015979915771. View

Wedlund P, Aslanian W, Jacqz E, McALLISTER C, Branch R, Wilkinson G . Phenotypic differences in mephenytoin pharmacokinetics in normal subjects. J Pharmacol Exp Ther. 1985; 234(3):662-9. View

Eichelbaum M, Mikus G, Vogelgesang B . Pharmacokinetics of (+)-, (-)- and (+/-)-verapamil after intravenous administration. Br J Clin Pharmacol. 1984; 17(4):453-8. PMC: 1463390. DOI: 10.1111/j.1365-2125.1984.tb02371.x. View

Evans A, Nation R, Sansom L, Bochner F, Somogyi A . Stereoselective drug disposition: potential for misinterpretation of drug disposition data. Br J Clin Pharmacol. 1988; 26(6):771-80. PMC: 1386594. DOI: 10.1111/j.1365-2125.1988.tb05318.x. View

ARIENS E . Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur J Clin Pharmacol. 1984; 26(6):663-8. DOI: 10.1007/BF00541922. View

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; 18(5):733-40. PMC: 1463564. DOI: 10.1111/j.1365-2125.1984.tb02536.x. View

Ward S, Walle T, Walle U, Wilkinson G, Branch R . Propranolol's metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities. Clin Pharmacol Ther. 1989; 45(1):72-9. DOI: 10.1038/clpt.1989.11. View

10.

Drayer D . Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview. Clin Pharmacol Ther. 1986; 40(2):125-33. DOI: 10.1038/clpt.1986.150. View

11.

Giacomini K, Nelson W, Pershe R, Valdivieso L, Blaschke T . In vivo interaction of the enantiomers of disopyramide in human subjects. J Pharmacokinet Biopharm. 1986; 14(4):335-56. DOI: 10.1007/BF01059195. View

12.

PFEIFFER C . Optical isomerism and pharmacological action, a generalization. Science. 1956; 124(3210):29-31. DOI: 10.1126/science.124.3210.29. View

13.

Toon S, Low L, Gibaldi M, TRAGER W, OReilly R, Motley C . The warfarin-sulfinpyrazone interaction: stereochemical considerations. Clin Pharmacol Ther. 1986; 39(1):15-24. DOI: 10.1038/clpt.1986.3. View

14.

Hendel J, BRODTHAGEN H . Entero-hepatic cycling of methotrexate estimated by use of the D-isomer as a reference marker. Eur J Clin Pharmacol. 1984; 26(1):103-7. DOI: 10.1007/BF00546716. View

15.

Jamali F, Mehvar R, Pasutto F . Enantioselective aspects of drug action and disposition: therapeutic pitfalls. J Pharm Sci. 1989; 78(9):695-715. DOI: 10.1002/jps.2600780902. View

16.

Jacqz E, Hall S, Branch R, Wilkinson G . Polymorphic metabolism of mephenytoin in man: pharmacokinetic interaction with a co-regulated substrate, mephobarbital. Clin Pharmacol Ther. 1986; 39(6):646-53. DOI: 10.1038/clpt.1986.113. View

17.

Hutt A, Caldwell J . The metabolic chiral inversion of 2-arylpropionic acids--a novel route with pharmacological consequences. J Pharm Pharmacol. 1983; 35(11):693-704. DOI: 10.1111/j.2042-7158.1983.tb02874.x. View

18.

Eichelbaum M . Pharmacokinetic and pharmacodynamic consequences of stereoselective drug metabolism in man. Biochem Pharmacol. 1988; 37(1):93-6. DOI: 10.1016/0006-2952(88)90758-7. View

19.

Jamali F, Singh N, Pasutto F, Russell A, Coutts R . Pharmacokinetics of ibuprofen enantiomers in humans following oral administration of tablets with different absorption rates. Pharm Res. 1988; 5(1):40-3. DOI: 10.1023/a:1015811428066. View

20.

Kupfer A, Roberts R, Schenker S, Branch R . Stereoselective metabolism of mephenytoin in man. J Pharmacol Exp Ther. 1981; 218(1):193-9. View