Enantiopure drug

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An enantiopure drug is a pharmaceutical that is available in one specific enantiomeric form. Most biological molecules (proteins, sugars, etc.) are present in only one of many chiral forms, so different enantiomers of a chiral drug molecule bind differently (or not at all) to target receptors. One enantiomer of a drug may have a desired beneficial effect while the other may cause serious and undesired side effects, or sometimes even beneficial but entirely different effects.[1] Advances in industrial chemical processes have made it economical for pharmaceutical manufacturers to take drugs that were originally marketed as a racemic mixture and market the individual enantiomers, either by specifically manufacturing the desired enantiomer or by resolving a racemic mixture. On a case-by-case basis, the U.S. Food and Drug Administration (FDA) has allowed single enantiomers of certain drugs to be marketed under a different name than the racemic mixture.[2] Also case-by-case, the United States Patent Office has granted patents for single enantiomers of certain drugs. The regulatory review for marketing approval (safety and efficacy) and for patenting (proprietary rights) is independent, and differs country by country.

Examples[edit]

The following table lists pharmaceuticals that have been available in both racemic and single-enantiomer form.

Racemic mixture Single-enantiomer
Amphetamine (Benzedrine) Dextroamphetamine (Dexedrine)
Bupivacaine (Marcain) Levobupivacaine (Chirocaine)
Cetirizine (Zyrtec / Reactine) Levocetirizine (Xyzal)
Citalopram (Celexa / Cipramil) Escitalopram (Lexapro / Cipralex)
Ibuprofen (Advil / Motrin) Dexibuprofen (Seractil)
Methylphenidate (Ritalin) Dexmethylphenidate (Focalin)
Milnacipran (Ixel / Savella) Levomilnacipran (Fetzima)
Modafinil (Provigil) Armodafinil (Nuvigil)
Ofloxacin (Floxin) Levofloxacin (Levaquin)
Omeprazole (Prilosec) Esomeprazole (Nexium)
Salbutamol (Ventolin) Levalbuterol (Xopenex)
Zopiclone (Imovane) Eszopiclone (Lunesta)

The following are cases where the individual enantiomers have markedly different effects:

  • Thalidomide: Thalidomide is racemic. One enantiomer is effective against morning sickness, whereas the other is teratogenic. However, the enantiomers are converted into each other in vivo.[3] Dosing with a single-enantiomer form of the drug will still lead to both the D and L isomers eventually being present in the patient's serum and thus would not prevent adverse effects (though it might reduce them if the rate of in vivo conversion can be slowed).
  • Ethambutol: Whereas one enantiomer is used to treat tuberculosis, the other causes blindness.
  • Naproxen: One enantiomer is used to treat arthritis pain, but the other causes liver poisoning with no analgesic effect.
  • Steroid receptor sites also show stereoisomer specificity.
  • Penicillin's activity is stereodependent. The antibiotic must mimic the D-alanine chains that occur in the cell walls of bacteria in order to react with and subsequently inhibit bacterial transpeptidase enzyme.
  • Only L-propranolol is a powerful adrenoceptor antagonist, whereas D-propranolol is not. However, both have local anesthetic effect.
  • The L-isomer of Methorphan, levomethorphan is a potent opioid analgesic, while the D-isomer, dextromethorphan is a dissociative cough suppressant.
  • (S)-(–) isomer of carvedilol, a drug that interacts with adrenoceptors, is 100 times more potent as beta receptor blocker than (R)-(+) isomer. However, both the isomers are approximately equipotent as alpha receptor blockers.
  • The D-isomers of amphetamine and methamphetamine are strong CNS stimulants, while the L-isomers of both drugs lack appreciable CNS(central nervous system) stimulant effects, but instead stimulate the peripheral nervous system. For this reason, the Levo-isomer of methamphetamine is available as an OTC nasal inhaler in some countries, while the Dextro-isomer is banned from medical use in all but a few countries in the world, and highly regulated in those countries who do allow it to be used medically.
  • Ketamine is commonly composed of R & S enantiomers that have different dissociative and hallucinogenic properties, whereas the S enantiomer Esketamine is more potent in isolation as a dissociative.

See also[edit]

References[edit]

  1. ^ E. J. Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology European Journal of Clinical Pharmacology 26 (1984) 663-668. doi:10.1007/BF00541922 Preview: [1]
  2. ^ US FDA's policy statement on the development of new stereoisomeric drugs
  3. ^ Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL (2004). "Clinical pharmacokinetics of thalidomide". Clin Pharmacokinet. 43 (5): 311–327. doi:10.2165/00003088-200443050-00004. PMID 15080764.