Skip to main content
SpringerLink
Log in

Detection of naproxen and its metabolites in fish bile following intraperitoneal and aqueous exposure

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

Purpose

The anti-inflammatory drug naproxen (NPX) has been found as a micropollutant in river water downstream the discharge points of wastewater treatment plants (WWTP). In this study, rainbow trout (Oncorhynchus mykiss) was exposed to NXP and the uptake and metabolism of the drug was studied.

Methods

Following exposure through intraperitoneal injection (i.p., 0.5 mg NPX/100 g fish biomass) and through water (1.6 μg L−1), the bile was collected and analyzed with various LC-MS/MS methods. The identification of the formed metabolites in i.p. injected fish was based on the exact mass determinations by a time-of-flight mass analyzer (Q-TOF-MS) and on the studies of fragments and fragmentation patterns of precursor ions by an ion trap mass analyzer (IT-MS).

Results

No matter the exposure route, the main metabolites were found to be acyl glucuronides of NPX and of 6-O-desmethylnaproxen. Also, unmetabolized NPX was detected in the bile. The total bioconcentration factors (BCFtotal-bile) of NPX and the metabolites in the bile of fish exposed through water ranged from 500 to 2,300.

Conclusion

The findings suggest that fish living downstream WWTPs may take up NPX and metabolize the compound. Consequently, NPX and its metabolites in bile can be used to monitor the exposure of fish to NPX.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Scheme 1
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Aresta A, Carbonara T, Palmisano F, Zambonin CG (2006) Profiling urinary metabolites of naproxen by liquid chromatography–electrospray mass spectrometry. J Pharm Biomed Anal 41:1312–1316. doi:10.1016/j.jpba.2006.02.041

    Article  CAS  Google Scholar 

  • Brooks BW, Chambliss CK, Stanley JK, Ramirez A, Banks KE, Johnson RD, Lewis RJ (2005) Determination of select antidepressants in fish from an effluent-dominated stream. Environ Toxicol Chem 24:464–469. doi:10.1897/04-081R.1

    Article  CAS  Google Scholar 

  • Brown JN, Paxéus N, Förlin L, Larsson DGJ (2007) Variations in bioconcentration of human pharmaceuticals from sewage effluents into fish blood plasma. Environ Toxicol Pharmacol 24:267–274. doi:10.1016/j.etap.2007.06.005

    Article  CAS  Google Scholar 

  • Daneshvar A, Svanfelt J, Kronberg L, Weyhenmeyer GA (2010) Winter accumulation of acidic pharmaceuticals in a Swedish river. Environ Sci Pollut Res 17:908–916. doi:10.1007/s11356-009-0261-y

    Article  CAS  Google Scholar 

  • EMEA (2006) Guideline on environmental impact assessment for veterinary medicinal products in support of the VICH Guidelines GL6 and GL38. EMEA/CVMP/ERA/418282/2005-Consultation, London, pp 1–59

  • Falany CN, Ström P, Swedmark S (2005) Sulphation of o-desmethylnaproxen and related compounds by human cytosolic sulfotransferases. Br J Clin Pharmacol 60:632–640. doi:10.1111/j.1365-2125.2005.02506.x

    Article  CAS  Google Scholar 

  • Fent K, Weston AA, Caminarada D (2006) Ecotoxicology of human pharmaceuticals. Aquat Toxicol 76:122–159. doi:10.1016/j.aquatox.2005.09.009

    Article  CAS  Google Scholar 

  • Ferrari B, Paxeus N, Lo Giudice R, Pollio A, Garric J (2003) Ecotoxicological impact of pharmaceuticals found in treated wastewaters: study of carbamazepine, clofibric acid, and diclofenac. Ecotoxicol Environ Saf 55:359–370. doi:10.1016/S0147-6513(02)00082-9

    Article  CAS  Google Scholar 

  • Fick J, Lindberg RH, Parkkonen J, Arvidsson B, Tysklind M, Larsson DGJ (2010) Therapeutic levels of levonorgestrel detected in blood plasma of fish: results from screening rainbow trout exposed to treated sewage effluents. Environ Sci Technol 44:2661–2666. doi:10.1021/es903440m

    Article  CAS  Google Scholar 

  • Fono LJ, Kolodziej EP, Sedlak DL (2006) Attenuation of wastewater-derived contaminants in an effluent-dominated river. Environ Sci Technol 40:7257–7262. doi:10.1021/es061308e

    Article  CAS  Google Scholar 

  • Haap T, Triebskorn R, Koehler H (2008) Acute effects of diclofenac and DMSO to Daphnia magna: immobilisation and hsp70-induction. Chemosphere 73:353–359. doi:10.1016/j.chemosphere.2008.05.062

    Article  CAS  Google Scholar 

  • Isidori M, Lavorgna M, Nardelli A, Parrella A, Previtera L, Rubino M (2005) Ecotoxicity of naproxen and its phototransformation products. Sci Total Environ 348:93–101. doi:10.1016/j.scitotenv.2004.12.068

    Article  CAS  Google Scholar 

  • Kallio J-M, Lahti M, Oikari A, Kronberg L (2010) Metabolites of the aquatic pollutant diclofenac in fish bile. Environ Sci Technol 44:7213–7219. doi:10.1021/es903402c

    Article  CAS  Google Scholar 

  • Lin AY-C, Reinhard M (2005) Photodegradation of common environmental pharmaceuticals and estrogens in river water. Environ Toxicol Chem 24:1303–1309. doi:10.1897/04-236R.1

    Article  CAS  Google Scholar 

  • Lin AY-C, Plumlee MH, Reinhard M (2006) Natural attenuation of pharmaceuticals and alkylphenol polyethoxylate metabolites during river transport: photochemical and biological transformation. Environ Toxicol Chem 25:1458–1464. doi:10.1897/05-412R.1

    Article  CAS  Google Scholar 

  • Lindqvist N, Tuhkanen T, Kronberg L (2005) Occurrence of acidic pharmaceuticals in raw and treated sewages and in receiving waters. Water Res 39:2219–2228. doi:10.1016/j.watres.2005.04.003

    Article  CAS  Google Scholar 

  • Levsen K, Schiebel H-M, Behnke B, Dötzer R, Dreher W, Elend M, Thiele H (2005) Structure elucidation of phase II metabolites by tandem mass spectrometry: an overview. J Chromatogr A 1067:55–72. doi:10.1016/j.chroma.2004.08.165

    Article  CAS  Google Scholar 

  • Mehinto AC, Hill EM, Tyler CR (2010) Uptake and biological effects of environmentally relevant concentrations of the nonsteroidal anti-inflammatory pharmaceutical diclofenac in rainbow trout (Oncorhynchus mykiss). Environ Sci Technol 44:2176–2182. doi:10.1021/es903702m

    Article  CAS  Google Scholar 

  • Meriläinen PS, Krasnov A, Oikari A (2007) Time- and concentration-dependent metabolic and genomic responses to exposure to resin acids in brown trout (Salmo trutta m. lacustris). Environ Toxicol Chem 26:1827–1835. doi:10.1897/06-521R.1

    Article  Google Scholar 

  • Metcalfe CD, Miao X-S, Koenig BG, Stuger J (2003) Distribution of acidic and neutral drugs in surface waters near sewage treatment plants in the lower great lakes, Canada. Environ Toxicol Chem 22:2881–2889. doi:10.1897/02-627

    Article  CAS  Google Scholar 

  • Mortensen RW, Corcoran O, Cornett C, Sidelmann UG, Troke J, Lindon JC, Nicholson JK, Hansen SH (2001) LC-1H NMR used for determination of the elution order of S-naproxen glucuronide isomers in two isocratic reversed-phase LC-systems. J Pharm Biomed Anal 24:477–485. doi:10.1016/S0731-7085(00)00453-2

    Article  CAS  Google Scholar 

  • National Agency for Medicines (2010) Finnish statistics on medicines. http://www.laakelaitos.fi/laaketieto/kulutustiedot. Accessed July 2010

  • Oikari OAJ (1986) Metabolites of xenobiotics in the bile of fish in waterways polluted by pulp mill effluents. Bull Environ Contam Toxicol 36:429–436. doi:10.1007/BF01623531

    Article  CAS  Google Scholar 

  • Quintana JB, Weiss S, Reemtsma T (2005) Pathways and metabolites of microbial degradation of selected acidic pharmaceutical and their occurrence in municipal wastewater treated by a membrane bioreactor. Water Res 39:2654–2664. doi:10.1016/j.watres.2005.04.068

    Article  CAS  Google Scholar 

  • Radke M, Ulrich H, Wurm C, Kunkel U (2010) Dynamics and attenuation of acidic pharmaceuticals along a river stretch. Environ Sci Technol 44:2968–2974. doi:10.1021/es903091z

    Article  CAS  Google Scholar 

  • Ramirez AJ, Mottaleb MA, Brooks BW, Chambliss CK (2007) Analysis of pharmaceuticals in fish using liquid chromatography–tandem mass spectrometry. Anal Chem 79:3155–3163. doi:10.1021/ac062215i

    Article  CAS  Google Scholar 

  • Ramirez AJ, Brain RA, Usenko S, Mottaleb MA, O’Donnel JG, Stahl LL, Wathen JB, Snyder BD, Pitt JL, Perez-Hurtado P, Dobbins LL, Brooks BW, Chambliss CK (2009) Occurrence of pharmaceuticals and personal care products in fish: results of a national pilot study in the United States. Environ Toxicol Chem 28:2587–2597. doi:10.1897/08-561.1

    Article  CAS  Google Scholar 

  • Selke S, Scheurell M, Shah MR, Hühnerfuss H (2010) Identification and enantioselective gas chromatographic mass-spectrometric separation of O-desmethylnaproxen, the main metabolite of the drug naproxen, as a new environmental contaminant. J Chromatorg A 1217:419–423. doi:10.1016/j.chroma.2009.11.095

    Article  CAS  Google Scholar 

  • Shipkova M, Armstrom VW, Oellerich M, Wieland E (2003) Acyl glucuronide drug metabolites: toxicological and analytical implications. Ther Drug Monit 25:1–16

    Article  CAS  Google Scholar 

  • Spahn-Langguth H, Benet LZ (1992) Acyl glucuronides revisited: is the glucuronidation process a toxication as well as a detoxification mechanism? Drug Metab Rev 24:5–47. doi:10.3109/03602539208996289

    Article  CAS  Google Scholar 

  • Ternes TA (1998) Occurrence of drugs in German sewage treatment plants and rivers. Water Res 32:3245–3260. doi:10.1016/S0043-1354(98)00099-2

    Article  CAS  Google Scholar 

  • Vieno NM, Tuhkanen T, Kronberg L (2005) Seasonal variation in the occurrence of pharmaceuticals in effluents from a sewage treatment plant and in the recipient water. Environ Sci Technol 39:8220–8226. doi:10.1021/es051124k

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This study was funded by Maj and Tor Nessling Foundation, the Finnish Graduate School in Environmental Science and Technology (EnSTe), and the Academy of Finland (no. 7109823). Antti Jylhä is acknowledged for his contribution in conducting the flow-though exposures.

Author information

Authors and Affiliations

  1. Laboratory of Organic Chemistry, Åbo Akademi University, Biskopsgatan 8, 20500, Åbo/Turku, Finland

    Jenny-Maria Brozinski & Leif Kronberg

  2. Department of Biological and Environmental Sciences, University of Jyväskylä, 40014, Jyväskylä, Finland

    Marja Lahti & Aimo Oikari

Authors
  1. Jenny-Maria Brozinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marja Lahti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aimo Oikari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leif Kronberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leif Kronberg.

Additional information

Responsible editor: Thomas Braunbeck

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brozinski, JM., Lahti, M., Oikari, A. et al. Detection of naproxen and its metabolites in fish bile following intraperitoneal and aqueous exposure. Environ Sci Pollut Res 18, 811–818 (2011). https://doi.org/10.1007/s11356-011-0441-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-011-0441-4

Keywords

Search

Navigation