Effects of carbamazepine on the central nervous system of zebrafish at human therapeutic plasma levels

The fish plasma model (FPM) facilitated the environmental risk assessment of human drugs by using existing data on human therapeutic plasma concentrations (HTPCs) and predicted fish plasma concentrations (FPCs). However, studies on carbamazepine (CMZ) with both the mode of action (MOA) based biological effects at molecular level (such as neurotransmitter and gene level) and measured FPCs are lacking. Bio-concentration ofCMZin adult zebrafish demonstrated that the FPM underestimated the bioconcentration factors (BCFs) in plasma at environmental CMZ exposure concentrations (1-100 mg/L). CMZ significantly increased Glu and GABA, decreased ACh and AChE as well as inhibited the transcription levels of gabra1, grin1b, grin2b, gad1b, and abat when the actual FPCs were in the ranges of 1/1000 HTPC to HTPC. It is the first read-across study of CMZ integrating MOA-based biological effects atmolecular level and FPCs. This study facilitates model performance against a range of different drug classes.

Automated summary

This study is the first to integrate MOA-based biological effects and FPCs of CMZ, finding that the FPM underestimates the bioconcentration factors of CMZ at environmental concentrations, and that CMZ has effects on neurotransmitters and gene levels in fish.