Importance of Toxicokinetics to Assess the Utility of Zebrafish Larvae as Model for Psychoactive Drug Screening Using Meta-Chlorophenylpiperazine (mCPP) as Example

Abstract

The number of new psychoactive substances (NPS) increases rapidly, harming society and fuelling the need for alternative testing strategies. These should allow the ever-increasing number of drugs to be tested more effectively for their toxicity and psychoactive effects. One proposed strategy is to complement rodent models with zebrafish (Danio rerio) larvae. Yet, our understanding of the toxicokinetics in this model, owing to the waterborne drug exposure and the distinct physiology of the fish, is incomplete. We here explore the toxicokinetics and behavioral effects of an NPS, meta-chlorophenylpiperazine (mCPP), in zebrafish larvae. Uptake kinetics of mCPP, supported by toxicokinetic modeling, strongly suggested the existence of active transport processes. Internal distribution showed a dominant accumulation in the eye, implying that in zebrafish, like in mammals, melanin could serve as a binding site for basic drugs. We confirmed this by demonstrating significantly lower drug accumulation in two types of hypo-pigmented fish. Comparison of the elimination kinetics between mCPP and previously characterized cocaine demonstrated that drug affinities to melanin in zebrafish vary depending on the structure of the test compound. As expected from mCPP-elicited responses in rodents and humans, zebrafish larvae displayed hypoactive behavior. However, significant differences were seen between zebrafish and rodents with regard to the concentration-dependency of the behavioral response and the comparability of tissue levels, corroborating the need to consider the organism-internal distribution of the chemical to allow appropriate dose modeling while evaluating effects and concordance between zebrafish and mammals. Our results highlight commonalities and differences of mammalian versus the fish model in need of further exploration.

Yolk Sac of Zebrafish Embryos as Backpack for Chemicals?

“…At present, internal chemical concentrations in fish embryos are determined from whole-body homogenates, 6,9 while the distribution of chemicals within the zebrafish embryo and its influence on the TK are rarely considered. 10 However, the yolk sac represents a compartment that is unique to the fish embryo. Differences in the composition of the yolk compared to that of the embryonic body, e.g., its higher phospholipoprotein content, may result in different sorption properties.…”

Tools for studying the metabolism of new psychoactive substances for toxicological screening purposes – A comparative study using pooled human liver S9, HepaRG cells, and zebrafish larvae

“…xenobiotics such as cytochrome P450 (CYP) oxygenases are identical (van Wijk et al, 2016) and zebrafish were already successfully used for metabolism studies of approved drugs (Kantae et al, 2016;Saad et al, 2017). So far, only one study has been published using zebrafish larvae in the NPS context; it was focused on distribution and toxicity studies of meta-chlorophenylpiperazine (mCPP) (Kirla et al, 2018). No metabolism studies of NPS using zebrafish larvae as in vivo model were done, yet.…”

Common anti-haemostatic medications increase the severity of systemic infection by uropathogenicEscherichia coli

“…The internal concentrations of drugs achieved by immersion exposure of zebrafish embryos to drugs needs to be determined for individual substances, however previous reports have reported a range of 1-20% peak absorption of small molecules [18, 19]. Our 10 μg/ml dose of aspirin delivered by immersion exposure is likely to be at the low end of the range of peak human therapeutic plasma concentrations 2-20 μg/ml [20, 21], while our 20 μg/ml dose of ticagrelor is likely to be on the high end of the peak human ticagrelor plasma concentration of 3.6 μg/ml for a 400 mg/day dose [22], and our 33 μM, roughly equivalent to 10 μg/ml, dose of warfarin is likely to be close to therapeutic human plasma levels <1 μg/ml [23, 24].…”