The increasing levels and frequencies at which active
pharmaceutical
ingredients (APIs) are being detected in the environment are of significant
concern, especially considering the potential adverse effects they
may have on nontarget species such as fish. With many pharmaceuticals
lacking environmental risk assessments, there is a need to better
define and understand the potential risks that APIs and their biotransformation
products pose to fish, while still minimizing the use of experimental
animals. There are both extrinsic (environment- and drug-related)
and intrinsic (fish-related) factors that make fish potentially vulnerable
to the effects of human drugs, but which are not necessarily captured
in nonfish tests. This critical review explores these factors, particularly
focusing on the distinctive physiological processes in fish that underlie
drug absorption, distribution, metabolism, excretion and toxicity
(ADMET). Focal points include the impact of fish life stage and species
on drug absorption (A) via multiple routes; the potential implications
of fish’s unique blood pH and plasma composition on the distribution
(D) of drug molecules throughout the body; how fish’s endothermic
nature and the varied expression and activity of drug-metabolizing
enzymes in their tissues may affect drug metabolism (M); and how their
distinctive physiologies may impact the relative contribution of different
excretory organs to the excretion (E) of APIs and metabolites. These
discussions give insight into where existing data on drug properties,
pharmacokinetics and pharmacodynamics from mammalian and clinical
studies may or may not help to inform on environmental risks of APIs
in fish.