Chiral Pharmaceuticals

Pharmaceuticals are chemicals used for diagnosis, treatment, alteration or prevention of disease, health condition, or structure/function of the human body, including veterinary drugs. They act by interaction with the binding site of the drug receptor which is a macromolecule such as enzymes, nucleic acids or membrane-bounded proteins, promoting the pharmacological action by the formation of a drug-receptor complex (Stringer 2006). Their action in humans is well described, but their mechanism and cumulative effects are mostly unknown in non-target organisms (Daughton and Ternes 1999).

Chiral pharmaceuticals are becoming of environmental concern because of the different pharmacokinetic, pharmacodynamics, toxicological and ecotoxicological properties occurring between enantiomers which may differently affect aquatic organisms. Concerning to pharmacokinetics, absorption, distribution (e.g. transport by passive or active way, in which the protein binding is important), metabolism and excretion can be different for each enantiomer since they represent biological processes in which binding proteins, membrane proteins, enzymes and other chiral molecules have an important role. Likewise, the pharmacodynamics involves the interaction with receptors like membrane proteins or enzymes which can be different for each enantiomer. Because chiral pharmaceuticals have normally different pharmacokinetic and pharmacodynamics properties, they have different dissociation constant from the binding site and different attachment to it leading to different biological response in quality or quantity (Campo et al. 2009).

In a review concerning the chirality in pharmaceuticals, Lima (1997) related few examples of chiral pharmaceuticals that can be used as racemates, as in the following cases:

(a) The pharmacologic activity of both enantiomers is the same (e.g., prometazine, antihistaminic). This effect is due to the equal pharmacokinetic and pharmaco-dynamics properties;

(b) One enantiomer is biologically more active than the other (e.g., propranolol, b-blocker). In this case both of enantiomers can reach the receptor, binding to it at the binding site with different dissociation constant, leading to a stronger attachment of one enantiomer;

(c) One of the enantiomers antagonizes the side effects of the other (e.g., indacrinone).

In others cases there are drugs that should be commercialized only as a single enantiomer, mostly due to the association of the enantiomers to different receptors, leading to different responses where (Mannschreck et al. 2007) :

(a) One enantiomer is biologically active and the other has no activity (e.g., a-metildopa);

(b) One enantiomer is biologically active and the other is antagonist (e.g., picenadol) (Franz et al. 1990);

(c) The pharmacologic activity of enantiomers is different (e.g., propoxyphene: analgesic and antitussive effects);

(d) One enantiomer has side effects (e.g., L-Dopa).

Table 1.1 shows few chiral pharmaceuticals that can be used as racemates and/or enantiopure formulations, depending on the effects of each enantiomer.

The recent advances in stereoselective synthesis and chiral analysis led to an increase of the single enantiomers as drugs available in the market (Hutt 1998). The re-evaluation of the license of the enantiomeric pure drugs which were produced in a racemic mixture, called as chiral switching process, also collaborated to increase the use of single enantiomer (Cordato et al. 2003; Hutt and Valentová 2003; Caner et al. 2004). However the chiral switching is related to economical, legislation and patent aspects, apart from the evident pharmacologic and toxicological details. Some pharmaceutical companies promote the patenting of new enantiopure pharmaceuticals at the expiring of the patent of the racemic drug (Somogyi et al. 2004). This aspect is highlighted by these authors especially when companies start the marketing approval of the new enantiopure drug when the racemic drug patent is expiring avoiding the release of generics from other companies (Barreiro et al. 1997; Somogyi et al. 2004; Mannschreck et al. 2007). Besides the advantages of enantiopure pharmaceuticals, like lower therapeutic doses, more safety margin, less interindividual variability, less drug interactions and fewer side effects, chiral switching can lead to unexpected toxicity (Baker et al. 2002). As such, the therapeutic advantage of an enantiopure drug must be clinically proven to justify the cost increase of the new treatment instead of the use of racemates. The single enantiomer and the relative racemate should be compared concerning to pharma-cokinetics and toxicological studies (Hutt and Valentová 2003 ; Somogyi et al. 2004; Orlando et al. 2007). Fluoxetine is a noted example of a failed chiral switching. Both enantiomers of fluoxetine are potent inhibitors of the serotonin reuptake pump but the enantiomers of the metabolite norfluoxetine have differences in this activity, being (R)-norfluoxetine an inactive metabolite and (S)-norfluoxetine the active metabolite (Henry et al. 2005). The affinity of (R)-fluoxetine for human 5-HT2A and 5-HT;C receptor subtypes is high, unlike (^-fluoxetine, being (R)-fluoxetine an antagonist for these receptors leading to an increase of extracellular catecholamines, such as serotonine, dopamine and norepinephrine. (S)-norfluoxetine has a similar binding to the transporter and is recognized as an active metabolite whereas (R)-norfluoxetine is an inactive metabolite (Koch et al. 2002). Besides, (S)-norfluoxetine is a potent inhibitor of its metabolic enzyme and contributes significantly to the half-life of the racemate, being (R)-norfluoxetine less active regarding this enzyme (Stevens and Wrighton 1993). The chiral switching would be the way to develop a new license market of (R)-fluoxetine with the same indications as racemic fluoxetine, with a better half-life, a better selectivity for important receptor subtypes in depression mechanism and less drug-drug interactions, being a good improvement for clinical strategies. However, the development of the (R)-isomer of fluoxetine was abandoned after an unexpected cardiac side effect, at higher doses, identified at Stage II clinical trials (McConathy and Owens 2003). The company

Table 1.1 Examples of chiral pharmaceuticals used as racemates or as single enantiomers

Drug

Qualitative activity

Equal Different Mode of action Description

References

Promethazine X

Propranolol X

Warfarin

Methadone X

Bupivacaine X

Fluoxetine

Propoxyphene X

Indacrinone

Equal pharmaco-logic potency Different pharmacologic potency

Both enantiomers have pharmacological activity but one of them has less toxicity and less side effects Enantiomers have different pharmacological activity

One enantiomer antagonize the side effects of the other

Promethazine

Propranolol:

(-)-propranolol has a pharmacological activity 100 times superior to (+)-propranolol Warfarin: anticoagulant, with greater anticoagulant potency of (S)-warfarin Methadone:

(R)-methadone has higher affinity for the m-opioid receptor and longer plasma elimination half-life Bupivacaine: S (-)-bupivacaine has the same neural blocking characteristics, but has a higher margin of safety

Fluoxetine:

(R)-fluoxetine is an antidepressant and (S)-fluoxetine was tested for migraines prophylaxis Propoxyphene:

(+)-propoxyphene is analgesic and (-)-propoxyphene is antitussive Indacrinone:

(S)-indacrinone is natriuretic and (R)-indacrinone is uricosuric

Chen et al.

Choonara et al. (1986)

Huq (2007)

Steiner et al. (1998)

Cooper and Anders (1974)

(continued)

Table 1.1 (continued)

Drug

Qualitative activity Equal Different

Mode of action

Description

References

Ibuprofen

X

One enantiomer is

Ibuprofen: its

Mayer and

pharmacologi-

anti-inflammatory

Testa

cally active and

activity is almost

(1997)

the other doesn't

due to

have activity

(S)-ibuprofen

Cetirizine

X

Cetirizine: its

Mannschreck

antiallergic

et al. (2007)

activity is due to

(R)-cetirizine

Dopa

X

One enantiomer is

Dopa: L-dopa is used

Hutt and

pharmacologi-

in Parkinson's

Valentova

cally active and

disease and

(2003)

the other has

D-dopa has side

side effects

effects like nausea,

anorexia,

involuntary

movements and

granulocytopenia

Thalidomide

X

One enantiomer is

Thalidomide:

Smith (2009)

pharmacologi-

(R)-thalidomide

cally active and

was used for

the other is

insomnia and

toxic

nausea therapy;

(S)-thalidomide is

teratogenic

Picenadol

X

One enantiomer is

Picenadol: (+)-picen-

Franz et al.

pharmacologi-

adol is an opioid

(1990)

cally active and

agonist and

the other is

(-)-picenadol is a

antagonist

weak agonist/

antagonist

This table resumes the benefits and disadvantages depending on the pharmacological or side effect had hoped that (^-fluoxetine would replace fluoxetine, which was facing imminent expiration of its patent protection.

Thus there are many pharmaceutical drugs that are both commercialized at race-mic and enantiopure forms, as described in Table 1.2 (Tucker 2000; Hutt and Valentova 2003; Orlando et al. 2007).

There are also some pharmaceuticals, such as Non Steroid Anti-Inflammatory Drugs (NSAIDs), which suffer chiral inversion, e.g., propionic acid derivatives. These drugs act by inhibition of cyclo-oxygenase (COX) and consequently the synthesis of prostaglandins and thromboxanes. Except for naproxen (Fig. 1.6) they are

Table 1.2 Examples of new enantiopure pharmaceuticals, which racemates were not withdrawn from the market

Racemate Therapeutic class

Enantiopure pharmaceutical

Trade name

Citalopram

Ibuprofen

Ketoprofen

Bupivacaine

Cetirizine

Omeprazole

Ofloxacin

Salbutamol

Antidepressant Anti inflammatory Anti inflammatory Anaesthetic Antihistaminic Proton pump inhibitor Antimicrobial b2-adrenergic receptor agonist

(^)-citalopram (escitalopram) (^)-ibuprofen (dexibuprofen) (^)-ketoprofen (dexketoprofen) (^)-bupivacaine (levobupivacaine) (^)-cetirizine (levocetirizine) (¿^-omeprazole (esomeprazole) (¿^-ofloxacin (levofloxacin) (^)-salbutamol (levalbuterol)

Lexapro, Cipralex Seractil

Sympal, Ketesse Chirocaine Xyzal Nexium

Levaquin,Tavanic Xopenex

Fig. 1.7 Structure of (^)-ibuprofen (a) and (S)-ibuprofen (b)

Fig. 1.7 Structure of (^)-ibuprofen (a) and (S)-ibuprofen (b)

commercialized as racemates in most countries. Ibuprofen (Fig. 1.7) is a common example of a NSAIDs used for pain, inflammation, fever and arthritis, which is normally sold as racemate although S-(+)-ibuprofen is practically the responsible for the pharmacologic action. Moreover this drug, as other profens, suffers unidirectional conversion to the pharmacologic active S-(+)-enantiomer in vivo which difficult to obtain the enantiopure (S)-ibuprofen with a good percentage of conversion justifying the use of racemates. The disadvantage of the racemic ibuprofen is that (S)-ibuprofen has less gastric side effects than the racemic mixture; is more hydro-soluble leading to a more rapid action; the chiral inversion can originate interindividual variability in analgesia; and the accumulation of the intermediate (^)-ibuprofen-CoA in the chiral inversion, which can react with triglycerides leading to the accumulation at fatty tissue in the organism (Lima 1997; Tucker 2000; Bonabello et al. 2003; Carvalho et al. 2006; Chávez-Flores and Salvador 2009).

Another therapeutic option is the use of chiral drugs with an enantiomeric ratio different from 1 to improve the benefits of each enantiomer, when applicable. Enantiomeric Fraction (EF) is the proportion of the concentration of one enantiomer to the total concentration, expressing the relative concentration of an enantiomer's compound. Racemate exhibits an EF of 0.5 while an enantiomerically pure compound has a value of 0 or 1. Thus, a mixture of two enantiomers in a proportion different to 1:1 has an EF between 0 and 1 and different to 0.5. As an example, the advantage of the administration of a mixture of S0.75:R0.25 bupivacaíne rather than the racemate was reported, with the same anaesthetic properties and with less toxic-ity (Gongalves et al. 2003).

In this review we will focus on three pharmaceutical classes: Beta-blockers, Antidepressants and Non Steroid Anti-Inflammatory Drugs (NSAIDs), due to their persistence in the environment and respective ecological effects (Ternes 1998; Trenholm et al. 2006; Vanderford and Snyder 2006; Pérez and Barceló 2008; Fernández et al. 2010; Santos et al. 2010).

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