TY - JOUR
T1 - Enantiomer-specific in vitro biotransformation of select pharmaceuticals in rainbow trout (oncorhynchus mykiss)
AU - Connors, Kristin A.
AU - Du, Bowen
AU - Fitzsimmons, Patrick N.
AU - Chambliss, C. Kevin
AU - Nichols, John W.
AU - Brooks, Bryan W.
PY - 2013/11/1
Y1 - 2013/11/1
N2 - 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 (CLIN 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. Chirality 25:763-767, 2013,
AB - 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 (CLIN 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. Chirality 25:763-767, 2013,
KW - bioaccumulation
KW - comparative pharmacokinetics
KW - contaminants of emerging concern
KW - environmental risk assessment
KW - metabolic biotransformation
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U2 - 10.1002/chir.22211
DO - 10.1002/chir.22211
M3 - Article
C2 - 23893772
AN - SCOPUS:84886640700
SN - 0899-0042
VL - 25
SP - 763
EP - 767
JO - Chirality
JF - Chirality
IS - 11
ER -