Summary
Racemic therapeutics are fixed ratio mixtures of stereoisomers to be regarded biologically as different compounds. Usually only one of the isomers fully contributes to the therapeutics action, and the other is often classifiable as “isomeric ballast”. Due to differences in turnover and pharmacokinetics, the proportion of enantiomers (1:1 in the racemate) continuously changes in plasma. The implications of the neglect of stereoselectivity for various levels in the investigation of racemic drugs are discussed and summarized in Table 2.
The fact is that clinical investigators, Ethical Committees and regulatory authorities have for decades accepted invalid pharmacokinetic data on some 25% of therapeutics. That those racemates remain in use make the benefit of and necessity for kinetics generally questionable.
Exposure of patients to the “isomeric ballast” present in about 50% of the most commonly used drugs will probably containe for many decades. As a result of a change in attitude of the regulatory authorities, however, for new drugs the choice in future between the racemic therapeutic or the single isomeric ballast-free drug will largely be based on a critical evaluation of the chiral characteristics with regard to their therapeutic, toxicological and pharmacokinetic aspects.
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References
Ariëns EJ (1984) Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur J Clin Pharmacol 26: 663–668
Ariëns EJ, Soudijn W, Timmermans PBMWM (1982) Stereochemistry and biological activity of drugs. Blackwell Scientific Publications, Oxford, pp 1–190
Series on Chirality, Trends in Pharmacological Sciences (1986) 7: 20–24, 60–65, 112–115, 155–158, 200–205, 227–230, 281–301
Ariëns EJ, Wuis EW (1987) Bias in pharmacokinetics and clinical pharmacology. Clin Pharmacol Ther 42: 361–363
Ariëns EJ, Wuis EW, Veringa EJ (1988) Stereoselectivity of bioactive xenobiotics. A pre-Pasteur attitude in medicinal chemistry, pharmacokinetics and clinical pharmacology. Biochem Pharmacol 37: 9–18
Ariëns EJ (1990) Stereoselectivity in pharmacodynamics and pharmacokinetics. Schweiz Med Wochenschr 120: 131–134
Drayer DE (1986) Pharmacodynamic and pharmacokinetic differences between drug enantiomers in humans: an overview. Clin Pharmacol Ther 40: 125–133
Wainer IW, Drayer DE (1988) Drug stereochemistry. Analytical methods and pharmacology. Dekker, New York
Jamali F, Mehvar R, Pasutto FM (1989) Enantioselective aspects of drug action and disposition: Therapeutic pitfalls. J Pharm Sci 78: 695–715
Smith DF (1989) The stereoselectivity of drug action. Pharmacol Toxicol 65: 321–331
Evans AM (1988) Stereoselective drug disposition: potential for misinterpretation of drug disposition data. Br J Clin Pharmacol 26: 771–780
Ariëns EJ, v. Rensen JJS, Welling W (1988) Stereoselectivity of pesticides — biological and chemical problems. Elsevier, Amsterdam
Eichelbaum M, Gross S (1990) Stereoselectivity in drug action and disposition. N Engl J Med
Ariëns EJ (1991) Chirality and isomeric ballast in bio-active products: Proceedings 3rd Netherlands Biotechnology Congress Amsterdam, in press. Elsevier, Amsterdam
Lehmann FPA, Rodriques de Miranda JF, Ariëns EJ (1976) Stereoselectivity and affinity in molecular pharmacology. In: Jucker E (ed) Vol 20. Birkhäuser, Basel, pp 101–142
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: 733–740
Tokuma Y, Fujiwara T, Niwa T, Hashimoto T, Noguchi H (1989) Stereoselective disposition of nivaldipine, a new dihydropyridine calcium antagonist, in the rat and dog. Res. Comm. Chem Pathol Pharmacol 63: 249–262
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: 105–114
Levine RJ (1986) Ethics and regulation of clinical research, 2nd ed. Urban and Schwarzenberg, Baltimore, pp 393–429
Morganroth J (1987) New antiarrhythmic agents: Mexiletine, tocainide, flecainide, encainide and amiodarone. Rational Drug Therapy. Am Soc Pharm Exp Ther 21: 1–5
Soons PA, de Boer AG, van Brummelen P, Breimer DD (1989) Oral absorption profile of nitrendipine in healthy subjects: a kinetic and dynamic study. Br J Clin Pharmacol 27: 179–189
Harten J van Burggraaf J, Lichthart GJ, Brummelen P van, Breimer DD (1989) Single- and multiple-dose nisoldipine kinetics and effects in the young, the middle-aged, and the elderly. Clin Pharmacol Ther 45: 600–607
Dunselman PHJM, Edgar B, Scaf AHJ, Kuntze CEE, Wesseling H (1989) Pharmacokinetics of felodipine after intravenous and chronic oral administration in patients with congestive heart failure. Br J Clin Pharmacol 28: 45–52
Smith RL, Caldwell J (1988) Racemates towards a New Year solution? TIPS 9: 75–77
Pasteur L (1901) On the asymmetry of naturally occurring organic compounds, the foundations of stereochemistry. In: Richardson GM (ed) Memoirs by Pasteur, Van't Hoff, Le Bel and Wislicenus. American Book Co, New York, pp 1–33
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Ariëns, E.J. Racemic therapeutics — ethical and regulatory aspects. Eur J Clin Pharmacol 41, 89–93 (1991). https://doi.org/10.1007/BF00265897
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DOI: https://doi.org/10.1007/BF00265897