title: Enantiomer-specific in vitro biotransformation of select pharmaceuticals in rainbow trout (Oncorhynchus mykiss).
abstract: The occurrence of pharmaceuticals in the environment represents a challenge of emerging concern. Many pharmaceuticals are chiral compounds; however, few studies have examined the relative toxicity of pharmaceutical enantiomers to wildlife. Further, our understanding of stereospecific pharmacokinetics remains largely informed by research on humans and a few well-studied laboratory test animals, and not by studies conducted with environmentally relevant species, including fish. The objective of this study was to investigate whether rainbow trout display stereospecific in vitro metabolism of three common chiral pharmaceuticals. Metabolism by trout liver S9 fractions was evaluated using a substrate depletion approach, which provides an estimate of intrinsic hepatic clearance (CL(IN VITRO,INT)). No biotransformation was observed for rac-, R-, or S-fluoxetine. Ibuprofen, including both enantiomers and the racemic mixture, appeared to undergo slow metabolism, but the resulting substrate depletion curves did not differ significantly from those of inactive controls. Contrary to relative clearance rates in humans, S(-)-propranolol was more rapidly cleared than the R(+)-enantiomer. This work demonstrates that relative clearance rates and the effects of racemic mixtures in trout could not have been predicted based on human data. Additional research describing species differences and exploring tools for species extrapolation in biomedical and environmental studies is needed.
authors.affiliation: Department of Environmental Science, Baylor University, Waco, Texas; Center for Reservoir and Aquatic Systems Research, Baylor University, Waco, Texas; Institute of Biomedical Studies, Baylor University, Waco, Texas.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Connors
authors.forename: Bowen
authors.initials: B
authors.lastname: Du
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Fitzsimmons
authors.forename: C Kevin
authors.initials: CK
authors.lastname: Chambliss
authors.forename: John W
authors.initials: JW
authors.lastname: Nichols
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Brooks
mesh_terms: D000818:Animals; D001711:Biotransformation; D004785:Environmental Pollutants / Q000737:chemistry* / Q000378:metabolism*; D017686:Oncorhynchus mykiss / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D004785:Environmental Pollutants; D004364:Pharmaceutical Preparations
keywords: bioaccumulation; comparative pharmacokinetics; contaminants of emerging concern; environmental risk assessment; metabolic biotransformation