RH-3421 action and toxicokinetics in the trout: reduced brain involvement versus mammals

The action and distribution of the insecticidal dihydropyrazole RH-3421 was examined in the trout and mouse. RH-3421 antagonized the depolarizing effect of the Na(+) channel activator veratridine and inhibited K(+)-stimulated uptake of (45)Ca(++) through voltage-sensitive calcium channels in trout brain synaptosomes. RH-3421 was a weaker inhibitor of these cellular targets in fish brain compared to mammalian brain. [(14)C]RH-3421 distributed rapidly following systemic administration to trout. Trunk kidney, muscle, liver and fat are important sites of accumulation, however, accumulation of [(14)C]RH-3421 in trout brain was low and polar metabolites were only found in bile. Mice administered an equivalent dose accumulated [(14)C]RH-3421 more efficiently into brain, and overall metabolism was more extensive. In trout, the brain is unlikely to be a major site of action of dihydropyrazoles. Our data indicate that perturbation of neuronal sites outside of brain cannot be excluded as contributing to the comparatively high acute toxicity of dihydropyrazoles in fish.