Advertisement

Plasma Concentrations of Human Pharmaceuticals as Predictors of Pharmacological Responses in Fish

  • D. B. Huggett
  • J. F. Ericson
  • J. C. Cook
  • R. T. Williams

Abstract

Pharmaceuticals typically have specific enzyme and receptor-based modes of action, which are extensively studied in mammals during drug development. Based on the considerable evidence of enzyme/receptor conservation across species, a predictive model has been developed that links therapeutic mammalian plasma levels to pharmacological responses in fish. In this model, a measured human therapeutic plasma concentration (HTPC) is compared to a predicted steady state plasma concentration (FssPC) in fish, which results in an effect ratio (ER = HTPC/FssPC) being computed. The lower the ER, the greater the potential for a pharmacological response in fish. The model was applied to twenty-eight drugs representing 15 therapeutic classes. ER values ranged from ≤ 1 to ≥ 10 000, with the category that represented an ER ≥ 10 000 containing the largest number of compounds (12 of 28). The two compounds with an ER ≤ 1 (17β-oestradiol and 17α-ethinyloestradiol) have previously been identified in chronic ecotoxicity evaluations as being active in fish. To begin to validate this model, rainbow trout were exposed for 96 h to 900 ng ml−1 ibuprofen or 200 ng ml−1 carbamazepine. These exposures resulted in measurable levels of these two compounds in trout plasma. These data indicate that pharmaceuticals may partition from water into fish plasma. While additional model refinement is needed, the model can provide a framework and prioritisation tool for considering pharmaceutical responses in fish.

Keywords

Rainbow Trout Effect Ratio Teleost Species Japanese Medaka Chronic Response 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Buhler DR, Wang-Buhler JL (1998) Rainbow trout cytochrome P45os:purification, molecular aspects, metabolic activity, induction and role in environmental monitoring. Comp Biochem Phys C 121: 107–137Google Scholar
  2. Daughton CG, Ternes TA (1999) Pharmaceuticals and personal care products in the environment: agents of subtle change. Env Health Persp 107: 907–938Google Scholar
  3. De Lucchini S, Marracci S, Nardi I (2001) The serotonin 5–HT2B receptor from the puffer fish Tetradon fluviatilis: cDNA cloning, genomic organization and alternatively spliced variants. Mol Brain Res 97: 89–93CrossRefGoogle Scholar
  4. Desbrow C, Routledge EJ, Brighty G, Sumpter JP, Waldock MJ (1998) Identification of estrogenic chemicals in STW effluent. 1. Chemical fractionation and in vitro biological screening. Env Sci Technol 32: 1549–1558CrossRefGoogle Scholar
  5. European Agency for the Evaluation of Medicinal Products (EMEA) (2003) Environmental risk assessment of non-genetically modified organism (non-GMO) containing medicinal products for human use. (CPMP/SWP/4447/oo, draft CPMP discussion paper)Google Scholar
  6. FDA (United States Food and Drug Administration) (1998) Guidance for industry: environmental assessment of human drug and biologics applications. Center for Drug Evaluation and Research andGoogle Scholar
  7. Center for Biologics Evaluation and Research (http://www.fda.gov/cder/guidance/index.htm
  8. FDA (United States Food and Drug Administration) (2002) (http://www.fda.gov/ceder/guidance)
  9. Fitzsimmons PN, Fernadez JD, Hoffman AD, Nichols J (2002) Bronchial elimination of superhydrophobic organic compounds by rainbow trout ( Oncorhynchus mykiss ). Aquat Toxicol 55: 23–34Google Scholar
  10. Foran CM, Weston JJ, Slattery M, Brooks BW, Huggett DB (to be published) Reproductive assessment of Japanese medaka following a four week fluoxetine exposure. Arch Environ Con ToxGoogle Scholar
  11. Gamperl A, Wilkinson M, Boutilier R (1994) ß-adrenoreceptor in the trout heart: characterization, quantification and effects of repeated catecholamine exposure. Gen Comp Endocrinol 95: 259–272CrossRefGoogle Scholar
  12. Hardman J, Limbird L, Molinoff P, Ruddon R, Gilman A (1996) Goodman, and Gilman’s pharmacological basis of therapeutics, 9th edn. McGraw Hill, New York, NYGoogle Scholar
  13. Huang CH, Sedlak DL (2001) Analysis of estrogenic hormones in municipal wastewater effluent and surface water using enzyme-linked immunosorbent assay and gas chromatography/tandem mass spectrophotometry. Environ Toxicol Chem 20: 133–139CrossRefGoogle Scholar
  14. Huggett DB, Brooks BW, Peterson B, Foran CM, Schlenk D (2002) Toxicity of select beta-adrenergic receptor blocking pharmaceuticals (/3–blockers) to aquatic organisms. Arch Environ Con Tox 43: 229–235CrossRefGoogle Scholar
  15. Huggett DB, Cook JC, Ericson JF, Williams RT (to be published) Theoretical model for prioritizing potential impacts of human pharmaceuticals to fish. J Hum Ecol Risk AssessGoogle Scholar
  16. Kirchheiner J, Meineke I, Freytag G, Meisel C, Roots I, Brockmoller J (2002) Enantiospecific effects of cytochrome P45o 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. Clin Pharmacol Ther 72: 62–75CrossRefGoogle Scholar
  17. Kolpin DW, Furlong ET, Thurman EM, Zaugg SD, Barber LB, HT Buxton (2002) Pharmaceuticals, hormones and other organic wastewater contaminants in US streams, 1999–2000: a national reconnaissance. Environ Sci Technol 36a: 202–1211Google Scholar
  18. Länge R, Hutchinson TH, Croudace CP, Siegmund F, Schweinfurth H, Hampe P, Panter GH, Sumpter JP (2001) Effects of the synthetic estrogen 17 alpha-ethinylestradiol on the life cycle of the fathead minnow (Pimephales promelas). Environ Toxicol Chem 20: 1216–1227Google Scholar
  19. Menuet A, Pellegrini E, Anglade I, Blaise O, Laudet V, Kah O, Pakel F (2002) Molecular characterization of three estrogen receptor forms in zebrafish: binding characteristics, transactivation properties and tissue distributions. Biol Reprod 66: 1881–1892CrossRefGoogle Scholar
  20. Meyniel JP, Khan NA, Ferriere F, Deschaux P (1997) Indentification of lymphocyte 5–HT3 receptor subtype and its implication in fish T-cell proliferation. Immunol Lett 55: 151–160CrossRefGoogle Scholar
  21. Nava J, Segner H (2001) Estrogen-mediated suppression of cytochrome P4501A expression in rainbow trout hepatocytes: role of estrogen receptor. Chem Biol Interact 138: 285–298CrossRefGoogle Scholar
  22. Nickerson JG, Dugan SG, Drouin G, Moon TW (2001) A putative /32–adrenoceptor from the rainbow trout (Oncorhynuchus mykiss) Eur J Biochem 268: 6465–6472Google Scholar
  23. Nuwaysir EF, Bittner M, Trent J, Barrett JC, Afshari CA (1999) Microarrays and toxicology: The advent of toxicogenomics. Mol Carcinog 24: 153–159CrossRefGoogle Scholar
  24. Pearce RE, Vakkalagadda GR, Leeder JS (2002) Pathways of carbamazepine bioactivation in vitro 1: Characterization of human cytochromes P45o responsible for the formation of 2– and 3–hydroxylated metabolites. Drug Metab Dispos 30: 1170–1179CrossRefGoogle Scholar
  25. Physicians Desk Reference (2002) available at http://www.pdr.net/pdrnet/librarianGoogle Scholar
  26. Pinter J, Thomas P (1999) Induction of ovulation of mature oocytes by the maturation-inducing steroid 17a,20ß-dihydroxy-4–pregnen-3–one in the spotted seatrout. Gen Comp Endocr 115: 200–209CrossRefGoogle Scholar
  27. Reid S, Moon T, Perry S (1992) Rainbow trout hepatocyte ß-adrenoreceptors, catecholamines responsiveness and effects of cortisol. Am J Physiol 2: 794–799Google Scholar
  28. Ruyter B, Andersen, O, Dehli A, Farrants AK, Gjoen T, Thomassen MS (1997) Peroxisome proliferators activated receptors in atlantic salmon: effects on PPAR transcription and acyl-COA oxidase activity in hepatocytes by peroxisome proliferators and fatty acids. Biochim Biophys Acta 1348: 331–338CrossRefGoogle Scholar
  29. Rxlist (2002) Drug profile resources. (available at http://www.rxlist.com)Google Scholar
  30. Scarano LJ, Calabrese EJ, Kostecki PT, Baldwin LA, Leonard DA (1994) Evaluation of a rodent peroxisome proliferator in two species of freshwater fish, rainbow trout (Onchorynchus mykiss) and Japanese medaka (Oryzias latipes). Ecotox Environ Safe 29: 13–19CrossRefGoogle Scholar
  31. Senthilkumaran B, Okuzawa K, Gen K, Kagawa H (2001) Effects of serotonin, GABA and neuropeptide Y on seabream gonadotropin releasing hormone release in vitro from preoptic-anterior hypothalamus and pituitary of red seabream Pagrus major. J Neuroendocrinol 13: 395–400CrossRefGoogle Scholar
  32. Sochor J, Klimes J, Sedlacek J, Zahradnicek M (1995) Determination of ibuprofen in erythrocytes and plasma by high performance liquid chromatography. J Pharm Biomed Anal 13: 899–903CrossRefGoogle Scholar
  33. Sundin L, Daison W, Forster M, Axelsson M (1998) The role of 5–HT2 recptors in the gill vasculature of the Antarctic fish Pagothenia borchgrevinki. J Exp Biol 201: 2129–2138Google Scholar
  34. Synder SA, Keith TL, Verbugge DA, Synder EM, Gross TS, Kannan K, Giesy JP (1999) Analytical methods for detection of selected estrogenic compounds in aqueous mixtures. Environ Sci Technol 33: 2814–2820CrossRefGoogle Scholar
  35. Ternes TA (1998) Occurrence of drugs in German sewage treatment plants and rivers. Wat Res 32: 3245–3260CrossRefGoogle Scholar
  36. Ternes TA, Stumpf M, Mueller J, Haberer K, Wilken R, Servos M (1999) Behavior and occurrence of estrogens in municipal sewage treatment plants - I. Investigations in Germany, Canada and Brazil. Sci Total Environ 225: 81–90Google Scholar
  37. Tetans G, Lykkeboe G, Christensen N (1988) Potency of adrenaline and noradrenaline for the B-adrenergic proton extrusion from red blood cells of rainbow trout. J Exp Biol 134: 267–280Google Scholar
  38. Todo T, Ikeuchi T, Kobayashi T, Kajiura-Kobayashi H, Suzuki K, Yoshikuni M, Yamauchi K, Nagahama Y (2000) Characterization of a testicular 17a,2oß-dihydroxy-4–pregnen-3–one (a spermiation inducing steroid in fish) receptor from a teleost, Japanese eel ( Anguilla japonica ). FEBS Lett 465: 12–17Google Scholar
  39. Waring JF, Ciurlionis R, Jolly RA, Heindel M, Ulrich RG (2001) Microarray analysis of hepatotoxins in vitro reveals a correlation between gene expression profiles and mechanisms of toxicity. Toxicol Lett 120: 359–368CrossRefGoogle Scholar
  40. Winberg S, Overli O, Lepage 0 (2001) Suppression of aggression in rainbow trout by dietary L-tryptophan. J Exp Biol 204: 3867–3876Google Scholar
  41. Webb SF (2001) A data-based perspective on the environmental risk assessment of human pharmaceuticals I-collation of available ecotoxicity data. In: Kämmerer K (ed) Pharmaceuticals in the environment. Springer-Verlag, New YorkGoogle Scholar
  42. Wood C, Shelton G (1980) Cardiovascular dynamics and adrenergic responses of the rainbow trout in vivo. J Exp Biol 87: 247–270Google Scholar
  43. Wu C, Patino R, Davis KB, Chang X (2ooi) Localization of estrogen receptor alpha-and beta-mRNA in germinal and nongerminal epithelia of the channel catfish testis. Gen Comp Endocr 124: 12–20Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2004

Authors and Affiliations

  • D. B. Huggett
  • J. F. Ericson
  • J. C. Cook
  • R. T. Williams

There are no affiliations available

Personalised recommendations