Trout and Human Plasma Protein Binding of Selected Pharmaceuticals Informs the Fish Plasma Model

Abstract

Concerns are increasing that pharmaceuticals released into the environment pose a risk to nontarget organism such as fish. The fish plasma model is a read-across approach that uses human therapeutic blood plasma concentrations for estimating likely effects in fish. However, the fish plasma model neglects differences in plasma protein binding between fish and humans. Because binding data for fish plasma are scarce, the binding of 12 active pharmaceutical ingredients (APIs; acidic, basic, and neutral) to rainbow trout (Oncorhynchus mykiss) and human plasma was measured using solidphase microextraction (SPME). The plasma/water distribution ratios (D plasma/w ) of neutral and basic APIs were similar for trout and human plasma, differing by no more than a factor of 2.7 for a given API. For the acidic APIs, the D plasma/w values of trout plasma were much lower than for human plasma, by up to a factor of 71 for naproxen. The lower affinity of the acidic APIs to trout plasma compared with human plasma suggests that the bioavailability of these APIs is higher in trout. Read-across approaches like the fish plasma model should account for differences in plasma protein binding to avoid overor underestimation of effects in fish. For the acidic APIs, the effect ratio of the fish plasma model would increase by a factor of 5 to 60 if the unbound plasma concentrations were used to calculate the effect ratio. Environ Toxicol Chem 2020;00:1-10.

Pharmacokinetics and Bioavailability of Carprofen in Rainbow Trout (Oncorhynchus mykiss) Broodstock

“…The amount of total plasma protein in trout is half compared with that in mammals; therefore, the binding ratio of drugs to plasma proteins in fish is lower than in mammals [ 37 ]. Acidic drugs such as naproxen have a lower binding ratio to plasma proteins in trout (94.6%) than in mammals (>99.9%) [ 47 ]. Because carprofen is also weakly acidic (pKa: 4.3) [ 40 ], its binding to plasma proteins may be low in trout.…”

Quantitative In Vitro-to-In Vivo Extrapolation: Nominal versus Freely Dissolved Concentration

“…For the neutral and hydrophilic chemicals, caffeine and lamotrigine, EC 10,free was very close to EC 10,nom , and only weak binding to human plasma was reported, and consequently QIVIVE nom and QIVIVE free gave similar ratios (within a factor of 4, Figure ).…”

“…Table presents the originally published values and the type of plasma concentration used for the QIVIVE model. For the majority of the test chemicals, only C total,plasma was reported, and C free,plasma was calculated by eq using the plasma-water distribution ratio ( D plasma/w ) of the test chemical and previously measured total protein and lipid mass ( m prot+lip,plasma = 62.81 g) and water content ( V w,plasma = 950.3 mL) of 1 L human plasma …”

“…For the majority of the test chemicals, experimentally determined plasma-water distribution ratios ( D plasma/w ) were available from a previous study . For consistency, D plasma/w of telmisartan and labetalol was measured for the present study using the same experimental approach.…”

Pharmaceuticals in the Environment: Just One Stressor Among Others or Indicators for the Global Human Influence on Ecosystems?

“…This represents a considerable challenge for developing predictive toxicity models across various species to ensure that risk assessments are broadly applicable in all the environmental compartments in which we find pharmaceuticals. Even fish plasma models linking therapeutic concentrations of pharmaceuticals in humans and fish, first proposed nearly 20 years ago to enable fast-tracking of potential effects in nontarget species, still require further interrogation to validate their use in robust effects assessments (Henneberger et al, 2022).…”