I got an enquiry from a pharmacy student a few days ago. “Recently, I learned that Esomeprazole is the S form of Omeprazole. Esomeprazole is more effective than Omeprazole. How come the latter is still on the market?”In responding to this enquiry I looked at a paper by Sumithira et al titled “Drug chirality & its clinical significance evident,future for the development/separation of singleenantiomer drug from racemates- The chiral switch”, Int J Ad Pharm Gen Res 1(1)2013; 1-19.
Chiral drugs are made up of molecule with the same chemical structure, but different threedimensionalarrangements. Modern manufacturing has enabled thedevelopment of products containing a single molecular arrangement.The development of this single enantiomer from chiral drugs is known as chiralswitching.
Enantiomer of the same drug can have different pharmacodynamic andpharmacokinetic properties.Stereoisomers are molecules with one or more“chiral” centre that allow the possibility of formswith the same chemicalformula but differingspatial arrangements. Enantiomers are a type ofstereoisomer in which the molecules have twonon-superimposable mirror image forms. As ahand fits into a glove, only the right or lefthanded enantiomer may fit a molecular receptorat a drug’s desired site of action.
A compoundcontaining an equal proportion of eachenantiomer is called a racemic mixture.Naturalcompounds are often single enantiomers(levothyroxine, levodopa, L- noradernaline). Incontrast, many commercially synthesized drugs areracemic mixtures (adrenaline, warfarin, fluoxetine,omeprazole). Recent studies with various singleenantiomersproved fewer adverse effects, lessdoses, and much higher potency thanthe racemates. Over the last 10-15 yearssingle enantiomers versus racemic mixtures havebecome areas of considerable interest as a resultof advances in the chemical technologiesassociated with the synthesis, separation &analysis of the individual enantiomers present ina racemates.
The re-evaluation of racemates is to identifyagents with a cleaner pharmacological profile,improved safety and efficacy and ultimatelytherapeutic benefits in addition to commercialadvantages. The R-isomer of Omeprazole exhibits greater variability thanthe S-isomerin poor versus extensivemetabolizers of CYP2C19 substrates. The R-isomer is more dependent on CYP2C19. Thisresults in the less active R-enantiomerachieving higherconcentrations in poor metabolizers,which may in the long term causeadverse effects like gastric carcinoidsand enterochromaffin- like cellhyperplasia. The S-isomer could be metabolized by alternativepathways like CYP3A4 andsulfotransferases. The S-isomer is clinically moreeffective than the racemate.The unichiraldrug approved for use is Esomeprazole. For Odanesetron, the R-isomer hasno QTc prolongation. It is lesscardiotoxic than either S-Ondansetronor racemicondansetron. The R-isomer is more potent than the Sisomer. The S-isomer causes QTc prolongation. The unichiral drug approved for use is R-Ondansetron. For bupivacaine, the R-isomer causes cardiotoxic effects and toxic effectson the CNS. The S-isomer is lesscardiotoxic and has less toxiceffects on the CNS in comparison withboth dextrobupivacaine andbupivacaine itself. The S-isomer has a wide safetymargin than the racemate. The unichiral drug approved for use is Levobupivacaine.
Advantages of chiral switch include the removal of unwantedpharmacodynamic side effects and toxic effects residingexclusively in one enantiomer.Others include exposing the patient to lower dose withsame therapeutic effect, thus reducingmetabolic/renal/ hepatic drug load compared
to racemic drug administration. There is less drug interactions and even enantiomer–enantiomer druginteractions if present.It avoids the probability for bio-inversion. It facilitates easier assessment of efficacy and toxicitythrough pharmacokinetic/pharmacodynamics monitoring of the stereochemically pureactive enantiomer.If the enantiomers are sufficientlydifferent inpharmacological effects, it may bepossible to get a patent on one or both.
Chirality is increasingly being seen as the future way of treatment. Many pharmaceutical compounds are marketedas racemates. Some of them need to be used asracemates for optimum activity. (Labetalol &Nebivolol). Many racemates need to be separatedinto single enantiomers or chirally pure
components prefixed as R or S enantiomers.Drug candidates in which one enantiomer is“active” is referred to as “eutomer” and the other
enantiomer which is “inactive” is referred to as “distomer”. E.g. S-Atenolol beta blocking property residesin its S-form.Levocetirizine has antihistaminicprofile, while dextrocetirizineis essentiallyinactive. Levofloxacin’s antibacterial activityresides in the S enantiomer only.
Chiral switch has been proposed as means ofobtaining safer alternatives to existing racemates.Switching from existing racemates to one of itsisomers has provided safer alternatives to drugs,ranging from antihistamines like cetirizine toanaesthetics like ketamine.Some unichiral drugs are more potent thantheir racemates, e.g.Levosalbutamol, S-Atenolol, S-Ketamine, S-MetoprololLevobupivacaine, S-Omeprazole, S-Zopiclone, S-Pantoprazole,
Levocetirizine, R-Ondansetron,R-Fluoxetine.
The toxicological properties in a pair ofenantiomers can be identical or entirely different.Thalidomide prescribed to pregnant womento counter morning sickness, led to a tragedy inthe 1960‟s in Europe. Studies on the drug latersuggested that teratogenicity was caused by the S-enantiomerand that the R-enantiomer containedthe desired therapeutic activity.
Thalidomide and it analogs have been the subject of numerous studies. In 1998 the USFDAapproved its use for treating leprosy symptoms. Studies indicate some promising results for use intreating symptoms associated with AIDS, behcletdisease, Lupus, rheumatoid arthritis, inflammatorybowel disease etc.Tetramisole is a nematocide, first used underracemic form. Because of numerous side-effects(vertigo, headache, vomiting, abdominal pain)mainly due to d-isomer, therefore, only l-isomercalled levamisole is now used in medicine.In the case of citalopram, the S-enantiomer isprimarily responsible for antagonism of serotoninre-uptake while the R-enantiomer is 30 fold lesspotent.
Chirality influences drug delivery because asingle enantiomer or a non-racemic blend may have improved solubility, dissolution, andstability. In addition, many availablepharmaceutical excipients (cellulose) eithernaturally occur as single enantiomers or arederivatives of the latter chiral molecules.Carboxymethylcellulose calcium is a suspending agent, stabilizer and coating agent. Ethylcelluloseis a binder, coating material and viscosity enhancer. Hydroxyethyl cellulose is a viscosity builder, binder and dissolution modifier. Alginic acid is a binder, disintegrant and viscosity enhancer. Carrageenan is a sustained release matrix and a suspending agent. Beta-cyclodextrin is a complexing agent and dissolution enhancer.
USFDA recognised the growing importance ofchirality in drugs and published its policystatement for the development of newstereoisomeric drugs in the year 1992.It noted among others that appropriate manufacturing and controlprocedures should be used to assurestereoisomeric composition of a product, withrespect to identity, strength, quality and purity.
In an analysis of all single enantiomer drugslaunched as a percentage of chiral molecules, theratio increased from 31.6% in 1985-1988 to 89.8% in 2001- 2004. It is estimated that sales ofUnichiral drugs reached $ 200 billion in 2008. The chiralswitch process provides a strategy to extend theprofitable life of a pharmaceutical bestseller”,and may result in extended patent protection andprovide an advantage against genericcompetition. E.g. Omeprazole versus Esomeprazole.
EDWARD O. AMPORFUL
