Biodegradation of Non Steroid Antiinflammatory Drugs NSAIDs Betablockers and Antidepressants as Individual Enantiomers

There are many studies on microbial degradation of chiral pharmaceuticals in the environment as racemates (Trautwein et al. 2008; Benotti and Brownawell 2009; Calisto and Esteves 2009; Mascolo et al. 2010; Santos et al. 2010), however biodegradation studies of individual enantiomers are scarcer (Table 1.4) (Buser et al. 1999; Fono and Sedlak 2005; Fono et al. 2006; Matamoros et al. 2009; Winkler et al. 2001).

The distribution of worldwide approved drugs indicates that the use of single enantiomers has increased during the 1990s reaching about 60% in the 2001, exceeding the achirals. The racemic drugs represented the minority category and many of the top-selling drugs, are marketed as single enantiomers (Caner et al. 2004) . According to a recent survey, the distribution of the 15 Food and Drug Administration approved drugs in the period of January-August 2003 was 64% of single enantiomers, 14% racemates and 22% achirals (Fig. 1.8) (Caner et al. 2004). Taking this into account both the biodegradation studies and the method quantification are crucial to be done for single enantiomers.

Table 1.4 Biodégradation studies of individual enantiomers in the environmental

Method

Matrix

Biodégradation experiment

Observation

Sampling local Refs

GC/MS/MS

GC/MS

GC/MS/MS

GC/MS/MS

Lakes, rivers and North Sea; WWTP influent and effluent Rivers

WWTP influent and effluent

Trinity River; WWTP effluent

HPLC/MS/MS WWTP

GC/MS

HPLC/MS/MS

WWTP influent and effluent

Aerated lagoon and three terciary WWTP

Incubation of fortified lake water; Incubation of WWTP' influent with activated sludge (aerobic conditions) Incubation of a biofilm with raw river water Microcosms experiments with filtered secondary effluent

Microcosms experiments with river water to assess phototransformation and degradation in the dark

Microcosms experiments with synthetic and real wastewater

Degradation of ibuprofen was rapid and mostly biological mediated, with S-form being faster degraded in both experiments

(R)-ibuprofen was degraded faster than the

(S)-form of ibuprofen, the active one EF decreased in microcosms inoculated with activated sludge but remained constant in not inoculated or sterilized treatments EF decreased from the effluent to downstream, suggesting the biological mediated degradation

Switzerland and Buser et al. North Sea (1999)

Canada Winkler et al.

USA (California Fono and and Sedlak

New York) (2005) Texas Fono et al.

Canada

Spain and Denmark

EF changed from influent to effluent for all the tested drugs, except for metoprolol, salbuta-mol and sotalol (S)-ibuprofen was degraded faster under aerobic conditions, depending on the oxidation status of WWTP. In anaerobic conditions, EF remains constant. Enantioselective degradation of naproxen is similar under aerobic and anaerobic conditions EF changed over time for all drugs except to sotalol Canada in one of the WWTP'effluent. EF differed among the three WWTP suggesting variations on biodégradation, except for metoprolol

MacLeod et al. (2007) Matamoros et al. (2009)

MacLeod and Wong (2010)

Biodégradation needs attention concerning the enantiomeric degradation ratio, since microorganisms can degrade selectively one enantiomer, can alter their enantioselectivity, or can degrade both enantiomers which is more unlikely to happen. Microbial degradation can also promote the enantiomerization (Richardson 2006; Perez and Barcelo 2008)

EF enantiomeric fraction, WWTP waste water treatment plant, n.a. not applicable

Single Knuntionicrs B Achirals U Racemates

Fig. 1.8 Distribution of the 15 Food and Drug Administration-approved drugs in the period of January-August 2003. Note that the majority of the chiral drugs approved are single enantiomers (64%)

Propranolol, a b-blocker used for treatment of cardiovascular diseases, with annual sales of the brand Inderal® of about $30 billion (Intercontinental Marketing Services-Health report 2006; Bartholow 2010), is normally detected in surface waters and in WWTP effluents (Ternes 1998; Huggett et al. 2003; Fono and Sedlak 2005). Propranolol is an important tool to distinguish the raw and treated sewage since propranolol has an EF of 0.5 (racemic) in WWTP influent and significantly below 0.5 in WWTP effluent, suggesting that this pharmaceutical is enantiomerically selective degraded through the biological treatment (Fono and Sedlak 2005). In the same study, EF decreased in microcosms inoculated with activated sludge but remain constant in not inoculated or sterilized treatments. The same researchers found in microcosms experiments that the EF of metoprolol, an analogous b -blocker, decreased from the effluent to downstream, suggesting selective biological mediated degradation of enantiomers (Fono et al. 2006).

Atenolol is a b-blocker also used for treatment of cardiovascular diseases with annual sales of the brand Tenormin® of approximately $102 million (Intercontinental Marketing Services-Health report 2006) included in the Top 200 Prescription Drugs of 2009 of United States (Bartholow 2010) and was one of the 11 most frequently detected compounds in United States in drinking water, being classified as an indicator of Endocrine Disrupting Compounds and other organic pollutants contamination and an indicator of the treatment success of a WWTP (Benotti et al. 2009). In the same study, atenolol demonstrated to be persistent and poorly removed by WWTP when traditional chlorine disinfection was applied, however it was easy removed when the treatment occurred with ozone. Vanderford and Snyder (2006) reported the presence of atenolol in the final effluent of WWTP at concentrations above 800 ngL-1. The detection of atenolol in finished drinking water has also been reported (Trenholm et al. 2006). In a enantioselective evaluation of effluents of three different WWTP in Canada, the EF of atenolol was different for the different effluents, indicating that the different microbial communities can affect the enantioselec-tivity of the biodegradation (MacLeod and Wong 2010).

Despite the evidences of phototransformation of propranolol and atenolol and of biodegradation of atenolol in river water samples (Liu et al. 2009), they were found in more than 80% of sampling sites in a Spanish river along the four seasons of the year, remarking their persistence and their chronic use (Fernández et al. 2010). Due to the differences in the sorption coefficient of propranolol and atenolol, atenolol is likely to adsorb to sludge while propranolol does not show significant adsorption (Maurer et al. 2007). Reungoat et al. (2010) showed the improvement of the pharmaceuticals removal such as atenolol in WWTP with further treatments such as coagulation, flocculation, flotation and filtration, ozonation, activated carbon filtration and ozonation for disinfection.

Fluoxetine, an antidepressant of the group of Selective Serotonin Reuptake Inhibitors, is one of the most dispensed drugs in the world (Stanley et al. 2007). It was one of the most prescribed drugs included in the Top 200 of the United States (Bartholow 2010). Fluoxetine was found in surface waters, treated wastewater, raw influent and even in finished drinking water in United States and South Korea at ngL - 1 levels (Trenholm et al. 2006; Vanderford and Snyder 2006). Fluoxetine and also its active metabolite norfluoxetine have been detected in WWTP effluents and in surface waters (MacLeod et al. 2007). Fluoxetine was reported as a persistent pharmaceutical after chlorine treatment rather than ozone because of the more potent oxidant effect attributed to ozone (Westerhoff et al. 2005). In a dissipation study of five Selective Serotonin Reuptake Inhibitors in aquatic microcosms, fluoxetine was the most persistent (Johnson et al. 2005). In a study using batch incubation of seawater samples, Benotti and Brownawell (2009) included fluoxetine in the more labile group and considered that adsorption to suspended sediment was minimal. Paterson and Metcalfe (2008) studied the uptake and depuration of fluoxetine in freshwater fish species, Japanese medaka (Oryzias latipes), and found a half-life three times higher than in mammalian species and a lower ability to biodegrade and eliminate such drug and its metabolite norfluoxetine. So, fluoxetine can indicate a recalcitrant behaviour in biological tissues, suggesting the possible chronic effects (Paterson and Metcalfe 2008).

Ibuprofen, a NSAID used for pain, fever and rheumatism, is the third most popular clinically used drug in the world and one of the 200 drugs most prescribed in the Unites States in 2009 (Bartholow 2010). Some researchers reviewed the occurrence of ibuprofen in numerous sediment and aquatic compartments (Ali et al. 2009b) . Buser et al. (1999) detected ibuprofen in river, lakes and influents of WWTP, with a higher concentration of the pharmacologically active (S)-enantiomer. In the same study, the degradation behaviour was similar during incubation experiments in WWTP influent incubated with activated sludge and in lake water fortified with racemic ibuprofen, with a faster dissipation of the (S)-enantiomer, mostly biological mediated. Hijosa-Valero et al. (2010) reported the decrease of EF of ibuprofen, which is according to the biological-depending degradation (Hijosa-Valsero et al. 2010). Jones et al. (2007) studied a WWTP located in southern England with activated sludge in the secondary biological treatment. Ibuprofen was found in all samples with a removal efficiency of ca 80-90% indicating a biological mediated degradation. Matamoros et al. (2009) found differences in the behaviour of ibuprofen EF's under aerobic and anaerobic conditions. In predominantly aerobic wastewater treatment systems ibuprofen EF's decreased, showing that the (S)-form was predominantly degraded, depending on the oxidation status of WWTP. In contrast, the anaerobic conditions led to a similar degradation of both enantiomers. In the same study, the behaviour of naproxen EF's showed a similar pattern in degradation at both aerobic and anaerobic conditions making it a good indicator for removal efficiency in aerobic or anaerobic wastewater treatment systems (Matamoros et al.

2009). Mascolo et al. (2010) reported biodegradation of racemic-naproxen, with degradation rates slower in wastewater samples than in synthetic wastewater, probably due to the presence of other organic compounds.

Marco-Urrea et al. (2010) studied the biodegradation of naproxen by the white-rot fungus Trametes vesicolor reporting degradation of 95% from an initial concentration of 55 mgL-1, a concentration similar to that found in the environment (Marco-Urrea et al. 2010).

Musson et al. (2010) reported chemical degradation as possible mechanism of degradation of racemic-ibuprofen. In the same study, racemic-ibuprofen was more resistant to biological removal than in other studies probably due to the higher concentration tested (Musson et al. 2010).

The occurrence and removal of ibuprofen, naproxen, fluoxetine and its metabolite norfluoxetine were studied in a tertiary sewage treatment plant in Sweden (Zorita et al. 2009), being reported removal rates superior to 90% for these compounds and the higher load of ibuprofen (6.9 mgL-1) and naproxen (4.9 mgL-1) due to the great consumption. Fluoxetine and norfluoxetine were below their detection limits after primary treatment, being removed by adsorption to fat and primary sludge. The additional chemical treatment step improved the removal of these pharmaceuticals. Apart from the common mechanical and biological treatments, the tertiary treatment such as ozonation, flocculation, advanced oxidation, osmosis or ultrafiltration, is unusual in Europe because it is expensive (Zorita et al. 2009).

In a WWTP in Spain it was reported removal rates below 20% for propranolol and atenolol, 60% for fluoxetine and naproxen and 95% for ibuprofen (Rosal et al.

2010) . After ozonation, all of them were below the quantification limits in a few minutes of contact with low ozone doses (<50 mM, except for naproxen which was <220 mM), providing a superior removal of compounds that are relatively refractory to biological treatment such as propranolol and atenolol.

Thus, there are very few reports concerning enantioselective degradation of pharmaceuticals in the environment. It is important to include this issue mostly in the biodegradation studies due to the enantioselectivity of the biological processes to assess the more recalcitrant enantiomers and to relate with their ecotoxicity.

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