Nature of Chiral Drugs and Their Occurrence in Environment

Journal of Xenobiotics 2014; volume 4:2272

Nature of chiral drugs regarding the marketing of these racemic compounds.6,7 Now after 1992 FDA and 1994 EU Correspondence: Bhavtosh Sharma, and their occurrence guidelines, the pharmaceutical industries are Uttarakhand Science Education & Research in environment moving from racemates to single enan- Centre (USERC), 33/2 Vasant Vihar, Dehradun, tiomers.8-10 Therefore, the enantiomeric reso- Uttarakhand, India. Tel.: +91.135.2760297. Bhavtosh Sharma lution of the chiral compounds has now E-mail: [email protected] Uttarakhand Science Education & become an urgent need. As it has been estab- Research Centre, Dehradun, India lished that human body is highly chiral selec- Key words: chiral drug, racemization, analysis, tive and will interact differently with a racemic environment. drug. Moreover, human body metabolizes each drug enantiomer by a different route with dif- Acknowledgements: the author is thankful to the Director USERC for providing the necessary facil- Abstract ferent pharmacological activity because the enantiomer of a drug possesses distinct biolog- ities to complete this work. ical interactions and therefore different phar- Effectiveness of chiral drugs is very well Conflict of interests: the author declares no macological activities. Therefore, chirality has potential conflict of interests established against several lethal diseases. now become an essential part in research and The demand of chiral drugs is increasing day development of drugs. The separation and test- Received for publication: 9 February 2014. by day. Besides this, the racemization of some ing of the enantiomeric forms of chiral drugs Revision received: 8 April 2014. chiral drugs is also found in biological as well have become necessary due to their different Accepted for publication: 24 April 2014. as in environmental matrices. The analysis of potential, toxicity and nature in biological sys- This work is licensed under a Creative Commons chiral drugs has become a necessary Research tem as well as in environmental samples. The and Development Unit task for any analytical Attribution NonCommercial 3.0 License (CC BY- research and development task for chiral drugs NC 3.0). scientist, pharmaceutical institute or pharma is being done by scientists and researchers industry considering not only the specific role considering the several different issues asso- ©Copyright B. Sharma, 2014 of these drugs for better and suitable treat- ciated with drug or its enantiomer like its Licensee PAGEPress, Italy ment of any lethal disease but also for their racemic nature, enantiomeric synthesis, Journalonly of Xenobiotics 2014; 4:2272 occurrence and fate in environmental matri- analysis or resolution, dosage potential, side doi:10.4081/xeno.2014.2272 ces. The present article highlights the impor- effects, inactiveness in the biological system. tance, bioactivities, occurrence and fate of chi- While on the other hand some chiral drugs like ral drugs in environment. thalidomide, ibuprofen etc. are also reporteduse in human excretion as unmetabolized fractions, different environmental matrices. 11-15 as untreated waste from sewage treatment Currently, the growing attention is being plants or due to less efficiency of sewage treat- given for the development of effective chiral ment plant (STP), etc. Kasprzyk-Hordern and Introduction resolution methods, controlled enantioselec- Baker have studied the enantiomeric-specific tive chemical synthesis, determination of fate of many chiral drugs such as amphetamine, Any object which forms non-superimposable enantiomeric purity and pharmacodynamics. meta-amphetamine, ephedrine, pseu- mirror images and is deficient with symmetry Various techniques especially chiral chromato- doephedrine, atenolol, vanlafaxine during elements is known as chiral object. All amino graphic methods have been developed. waste water treatment and also in receiving acids, proteins, enzymes, carbohydrates etc. Besides, capillary zone electrophoresis, capil- water body. The authors also reported that the are chiral compounds in nature. Initially, Louis lary gel electrophoresis and capillary elec- stereoselectivity depends on the type of chiral Pasteur discovered the chiral chemistry in trochromatography have been established as drug, used technology and seasons. These facts 1948 during the separation of two isomers of powerful tools over chromatographic tech- clearly indicate the less efficiencies of STPs.18 sodium ammonium tartrate.1 Though, chirality niques for enantiomeric analytical studies in The occurrence of Ibuprofen enantiomeric com- possesses a key role not only in the existence environmental and biological samples both. position in surface water and waste water treat- of living beings such as plants and animals but Consumption of pharmaceuticals has ment plants using enantioselective gas chro- in pharmaceutical and other chemical indus- increased not only due to increasing human matography-mass spectrometric method.14 The tries. Most of the pharmaceutical compoundsNon-commercialpopulation but also due to the application of authors found that ibuprofen and its metabo- show the optical activity due to their asymmet- these compounds to prevent the fatal diseases lites were degraded up to 95% but the rate of ric nature. Now it has been established that in livestock. Diclofenac, aceclofenac, aceta- degradation of clofibric acid and diclofenac was only one of the two enantiomers i.e. eutomer is minofen and meloxicam drugs have been used found very less during the treatment process pharmacologically active while its counterpart as non-steroidal anti inflammatory drugs in due to the less efficiency of waste water treat- i.e. distomer generally creates side effects or livestock. Some fetal diseases of livestock like ment plants (WWTPs) for these drugs.14 The toxic effects or may inert. The significant bio- respiratory diseases, swine dysentery, and bac- occurrence of drugs and pharmaceuticals as logical activities of enantiomers of drugs have terial enteritis are being treated by using sev- well as their metabolites in municipal waste created an interest of scientific community to eral pharmaceuticals. Besides this, antimicro- water and finally in to aquatic system has study their pharmacological and toxicological bial drugs are also used in livestock.16 become a serious problem not only for aquatic effects.2-5 Therefore, the administration of Moreover, as per a US Department of organisms but for humans also.19 The impact of pharmacologically active enantiomer of drug Agriculture (USDA)’s survey of 2010, it is esti- pharmaceuticals on the environment has been possesses specific importance. Moreover, the mated that approximately 80% of breeder studied very less where as these compounds are United States Food and Drug Administration chicken farms in United States vaccinated pul- very hazardous for aquatic environment and (US FDA), European Committee for lets in opposition to Salmonella, bronchitis, introduced in to the environment through vari- Proprietary Medicinal Products and other drug and coccidiosis, among other fetal diseases.17 ous routes.20 Therefore, the present article controlling agencies have issued definite Besides, the drugs and pharmaceuticals are highlights the fate and occurrence of chiral guidelines to pharmaceutical industries being introduced in to the environment through pharmaceuticals in environmental matrices.

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ment may be point i.e. through domestic or their transformation products have been recog- Global chiral drug market industrial activities or may be non-point i.e. nized by advanced analytical tools such as liquid through agricultural activities etc. Hegeman chromatography (LC) or gas chromatography At present about 60-70% pharmaceuticals and Lanne25 have discussed the distribution (GC) in association with tandem mass spectro- are chiral drugs. The international market of pattern of chiral xenobiotics in environmental metric (MS/MS) detection.52 Further in another chiral synthesis, chiral analysis and chiral res- ecosystem. Some research work has been car- research, some β-blockers viz. atenolol, meto- olution is rising rapidly. However, according to ried out by researchers to understand the envi- prolol, propranolol, pindolol,( nadolol and a report, the Global Market of Chiral ronmental fate and toxicity of pharmacologi- sotalol), selective serotonin reuptake inhibitors Technology was $5.3 billion during 2011 year cally active compound of used drugs and phar- (citalopram and fluoxetine) and salbutamol and will come up to $7.2 billion approximately maceuticals in environment especially chiral were studied during wastewater treatment and at the end of year 2016.21 This statistics of chi- drugs. The enantiomers of chiral drugs can be the changes in their enantiomeric fractions ral market is sufficient to understand the fact different in their toxic nature because of their were observed as a result of treatment process. that the awareness about the importance of different pharmacological activity. Besides, the The authors observed that influent was chiral drug application is ever-increasing. degradation of chiral drugs in environment as enriched with R(+)-atenolol where as the efflu- Although pharma industries possess the major well as in waste water treatment process can ent was found racemic.53 part in global chiral market but biochemical, be stereoselective and various chiral products Matamoros and co-workers studied the agrochemical, food and flavor industries are of different toxicity can be formed. Although enantioselective degradation of ibuprofen dur- also adopting chiral technologies. Therefore, the studies on the occurrence and fate of drugs ing WWT process and reported that the degra- the chiral products either drugs, pharmaceuti- are very limited26-31 but their presence in the dation of ibuprofen depends on the oxidation cals, agrochemicals or chiral technologies environment can not be neglected.32 status of the plant while its degradation was have become the need of the time and their Many of the chiral drug compounds have not found enantioselective under anaerobic demand is increasing in the light of its poten- been occurred in water resources such as in conditions.54 Hühnerfuss and Shah reported tial importance and public welfare. river water, lakes, oceans and in ground water that metabolites of ibuprofen i.e. hydroxy- system also.33-35 Besides, the occurrence of ibuprofen and carboxyibuprofen were not only these compounds has been established in sedi- found in human body through different enzy- ments and soil systems also by several maticonly process but also observed in a STP and Important chiral drug researchers.36-40 Now a days, several chiral com- in rivers.55 Buser et al. reported the occurrence enantiomers and their pounds have been detected in several vegeta- of ibuprofen in river water and observed the bles, crops and in some other food products.41,42 more degradation of non-pharmacologically bioactivities Antibiotics, steroids, analgesic drugsuse are the active R-enantiomer of ibuprofen.14 most commonly studied pharmaceuticals. Anti- Commonly, β-blockers are being used for Several studies have reported that chiral inflammatories i.e. diclofenac, ibuprofen, the treatment of high blood pressure and to drug stereoisomers generally represent clear naproxen, ketoprofen, blood lipid regulators and treat the heart patients. These compounds act differences in their metabolic and pharmaco- their metabolites have been recently reported by competitive inhibition of β-adrenergic kinetic activities.22,23 Some of the important as toxic in respect of certain bacteria and receptors in the body. However, atenolol, pro- chiral drug enantiomers and their properties algae.43 Carbamazepine drug has been widely pranolol and metoprolol are reported as the specially bioactivities are given in Table 1.6,7,24 detected in the environment.26,28 Basically, most widely studied β-blockers in environmen- municipal effluents are the principal sources of tal studies. Most of the researchers have these pollutants.44-51 The conventional WWTPs reported about the stereoselective bio-degra- are not sufficiently able to treat municipal efflu- dation of β-blockers in aquatic system and dur- Chiral drugs in environment ents due to the hydrophilic nature of these com- ing waste water treatment process. However, pounds. However, emerging contaminants and several authors reported stereoselective bio- Chiral drug enantiomers are boon for a lethal disease but there are some examples that one of the enantiomer of these drugs is toxic and termed as chiral pollutant.Non-commercial Despite the above facts, the degradation of achiral Table 1. Chiral drug enantiomers and their bioactivities. drugs or pollutants can be changed into toxic metabolites or intermediate compounds under Chiral drug Enantiomer’s bioactivity (property) various environmental conditions through var- Ethambutol (S,S)-form is tuberculostatic agent ious kinetic or thermodynamic parameters. Ketamine (+)-enantiomer possess stronger anesthetic property However, it has been established that the degradation of these compounds take place in Albuterol (D)-form can provoke airway constriction and (L)-form avoids the side effects environment either by chemically or biologi- Morphine (-)-form has strong analgesic property cally at different rates. Generally, chiral xeno- Propanolol Only (S)-form possesses the β-adrenergic blocking activity biotics occur in dynamic equilibrium in a Propoxyphene α-D-form is analgesic and β-L-form is anti-tussive water body with sediments. Dynamic equilibri- Thalidomide (S)-form possesses the anti-nausea effects and (R)-form causes the um of chiral drugs in environment means a malformation of embryos in pregnant woman system with a steady state if the forward and Warfarin (-)-enantiomer is strong anticoagulant agent backward reactions proceed at the same rate. Due to the dynamic equilibrium of chiral drugs Penicillamine (R)-form is toxic and (S)-form has anti-arthritic activity in environment, these chemical species exist Dopa (L)-form is Parkinson’s disease agent while (D)-form creates side effects in more than one form. Non-steroidal anti (+)-form possesses more anti-inflammatory property The origin of chiral xenobiotics in environ- inflamatory drugs

[Journal of Xenobiotics 2014; 4:2272] [page 15] Review logical degradation of β-blockers during capillary isotachophoresis etc. On the other mental samples as given below in Table 3.52,65,66 (WWTP) treatment and in the aqueous envi- hand chromatographic chiral resolution tech- Table 4 shows the occurrence of ibuprofen con- ronment.56,57 The enantioselective degradation nique has also received the importance centrations in different environment matri- of three β-blockers such as metoprolol, through its liquid chromatographic method. ces.67-79 The chiral drug analysis in environ- atenolol and propranolol have been studied Liquid chromatography covers mainly high mental samples by chromatographic methods during waste water treatment and reported performance liquid chromatography, capillary including gas and liquid chromatographic that it was due to seasonal effect and selectiv- electrochromatography, supercritical chro- methods takes place through various chiral ity of micro organisms having the capability of matography, thin layer chromatography etc. recognition mechanisms depending on the degradation of the analyte.56 Besides this, the Besides this, ultra performance liquid chro- chiral selectors used. Liquid chromatographic authors also reported the different stereoselec- matography and ultra high performance liquid resolution of racemic compounds either phar- tivity of different WWTPs. chromatography are advanced techniques to maceuticals or agrochemicals have achieved a Stan and Linkerhägner has recognized the fulfil the aim. However, liquid chromatography great reputation in the ground of separation presence of clofibric acid abundantly in ground based chiral methods and chiral products are science.5,7,80-82 Chiral Drug analysis on different water samples of Berlin city in Germany, which fast in race at global scale. The most important chiral selectors occurs through some mecha- is a metabolite of the lipid regulating agents aspect in chiral resolution by high-perform- nisms like dipole induced dipole, hydrogen, π- clofibrate and etofibrate.58 Some reports have ance liquid chromatography is the application π interactions, Vander Waals forces etc. revealed that few drugs like ibuprofen, bezafi- of chiral stationary phases such as polysaccha- between analyte and chiral selectors depend- brate, metoprolol have been occurred in the rides, cyclodextrins, macrocyclic glycopeptide ing on the selection of method of analysis and environment i.e. in STP effluent and river antibiotics, crown ethers, proteins, Pirkle nature of analyte. water with more than 80% rate of elimina- types and ligand exchangers etc.7 Nano liquid tion.59,60 Hühnerfuss et al. have reported the chromatographic methods have been devel- enzymatic transformation processes of chiral oped and very significantly being used in chi- Futuristic aspects of chiral pharmaceuticals in the aquatic environment. ral drug analysis in environmental samples.64 Under this study, the authors have verified the Gas chromatography with mass spectrome- drugs various enzymatic metabolism of ibuprofen try i.e. GC-MS or tandem mass spectrometry and the formation of carboxyibuprofen and i.e. GC-MS/MS and liquid chromatography with Ononly the basis of above discussion, it can be hydroxyibuprofen in human body, in biological mass spectrometry (LC-MS) or with tandem said that chiral drugs have become an urgent treatment stage of STP and in river water sam- mass spectrometry (LC-MS/MS) are the need of the day due to several important rea- ples by using enantioselective GC analyses.61 advanced analytical and detection methods for sons like their improved therapeutic index, Gagnon and Lajeunesse detected the acidic the detection of chiral drugs and their enan-useless complex pharmacodynamics and pharma- pharmaceutical drugs such as clofibric acid, tiomers at nanogram per liter in samples from cokinetic profile, less drug toxicity, less or nil carbamazepine, diclofenac, ibuprofen and various environmental matrices. Some scien- side effects etc..9,83 But the proper disposal of naproxen in large quantity in primary treated tists have reported these analytical tools for sewage waste by advanced treatment plants of effluents i.e. from 77-2384 ng/L.62 The detected the detection of these compounds in environ- sufficient efficiencies is necessary to prevent concentrations of various drugs in inlet and outlet of waste water treatment plants are described in Table 2 and also described the less efficiency of WWTPs for some drugs.63 Table 2. Concentrations of various drugs in (ng L–1) inlet and outlet of waste water treatment plants. Drug Before WWTPs (inlet) After WWTPs (outlet) Chiral drug analysis Ibuprofen 516 266 The pure enantiomer of any drug or pharma- Propanolol 290 168 ceutical can be obtained by enantioselective Atenolol 400 395 synthesis but this approach is expensive.Non-commercialSotalol 185 167 Generally we get a racemic mixture in a syn- Ketoprofen 451 318 thesis but the resolution of the enantiomers Naproxen 99 108 from a racemate is necessary on preparative scale after the development of a method on Diclofenac 250 215 analytical scale. Besides this, chiral resolution Acetaminophen 10,194 2102 is not only necessary to control synthesis and Cloﬁbrate 72 28 enantiomeric purity but for checking the Carbamazepine 420 410 racemization of drug enantiomer and pharma- WWTPs, waste water treatment plants. cokinetic study. Despite the presence of some classical methods of chiral separation such as preferential crystallization and enzymatic degradation (biotransformation), some Table 3. Analytical methods for the detection of chiral drugs in environmental samples. advanced techniques have been developed for Sr. No. Analytical method this purpose including chromatographic, elec- 1 GC-MS or GC-MS/MS without derivatization trophoretic, biosensor and spectroscopic tools. Electrophoretic method for chiral separation 2 GC-MS or GC-MS/MS with derivatization includes its various forms like capillary gel 3 LC-MS or LC-MS/MS electrophoresis, capillary zone electrophoresis, GC, gas chromatography; MS/MS, tandem mass spectrometric; LC, liquid chromatography.

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