Enantiopure Medications: Are Chiral Drugs More Effective?

Many newer drugs now available or being developed are based on the principle that enantiomers of a drug may work differently in the body. Drug companies develop ways to purify one enantiomer and produce a medication using only that enantiomer. This type of drug is called an enantiopure or enantiomeric medication.

For some drugs, only one enantiomer is effective. A pure enantiomer of the effective form would, in theory, only require half the effective dose of a 50/50 racemic mixture. The clinical picture is more complicated.

For example, the results of studies of enantiopure escitalopram versus racemic citalopram have mixed results. Some single studies show that escitalopram is no better or worse than citalopram and other SSRI antidepressants (e.g. Svensson & Mansfield 2004); others, including meta-analyses (studies of studies), show it to be more effective or to have fewer side effects (e.g. Kennedy et al. 2006).

Armodafinil (Nuvigil) is a newly-approved drug that is the R-enantiomer of modafinil (Provigil). This enantiomer stays in the body longer than the S-enantiomer, so theoretically, it may work better or longer than racemic modafinil. However, while studies have proved that armodafinil is effective, there are no data yet on whether it actually works better than racemic modafinil.

The most dramatic case of enantiomers that have different effects in the body is that of thalidomide. "Right-handed" thalidomide stops nausea and vomiting, while "left-handed" thalidomide causes severe birth defects. Thousands of babies were born in the late 1950s and early 1960s, mostly in Europe, with birth defects caused by the thalidomide their mothers were given for morning sickness. (Even if pregnant women had access to the "safe" enantiomer, the body changes it back and forth into both enantiomers (Teo et al. 2004), so it would still cause birth defects.)

Not all medications benefit from being enantiopure. For example, ibuprofen is a racemic drug, but the body has an enzyme that converts one enantiomer to the other, so there is no benefit to purifying one enantiomer.

There are several rather arbitrary ways to name an enantiomer. The various rule sets are not related to each other but use similar terminology, so they can be very confusing. In the R/S system, based on the specific atoms in the molecule, one configuration is called "rectus" (R- for short) and the other is called "sinister" (S- for short), from the Latin words for right and left. In the D/L system, which is related to how the molecule compares to the chiral molecule glyceraldehyde, one version is called "dextro-" (D- for short) and its mirror image is called "levo-" (L- for short) (from another pair of Latin words for right and left). In the (+/-) system, also called the d-/l- system (which should not be confused with the D-/L- system), the assignment is based on how the enantiomer bends polarized light.

An enantiopure medication's generic name usually just adds its prefix (R-, S-, dextro-, or levo-) to the generic name of the racemic version. R- and S- are usually converted to the easily pronouncible "ar" and "es." So S-omeprazole, an enantiopure version of omeprazole, is usually spelled esomeprazole.

When deciding on the brand name of an enantiomeric medication, drug companies sometimes try to make the new version sound like a completely novel development. For example, omeprazole, a drug that treats stomach problems, is marketed under the brand name Prilosec, while its S-enantiomer, esomeprazole, is called Nexium. In other cases, the new brand name is chosen to make the drug sound like a newer or better version of a familiar medication. For example, escitalopram is the S-enantiomer of citalopram. Their brand names, Lexapro and Celexa (respectively), are similar. Armodafinil is the R-enantiomer of modafinil; their respective brand names, Nuvigil and Provigil, make the purified version sound like a "new" version of Provigil.

• Sidney H. Kennedy, Henning F. Andersen, and Raymond W. Lam. "Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis." J Psychiatry Neurosci. 2006 March; 31(2): 122–131. S. Svensson and P. R. Mansfield. "Escitalopram: superior to citalopram or a chiral chimera?" Psychother Psychosom. 2004 Jan-Feb;73(1):10-6. S. K. Teo et al. "Clinical pharmacokinetics of thalidomide." Clin Pharmacokinet. 2004;43(5):311-27.