Toxicokinetics and postmortem redistribution of amantadine in rats

TL;DR

This study examines how amantadine distributes in rat tissues and changes after death, highlighting the importance of using multiple tissues for accurate toxicological analysis.

Contribution

The study provides new toxicokinetic and postmortem redistribution data for amantadine across multiple tissues in rats.

Findings

Amantadine shows high tissue-specific distribution, with the liver and kidney having the highest exposure.

Postmortem redistribution is significant and influenced by dose, postmortem interval, and storage temperature.

Liver-to-muscle and spleen-to-brain concentration ratios show consistent trends, aiding toxicological interpretation.

Abstract

Amantadine (AMD) is an antiviral and antiparkinsonian drug with a narrow therapeutic window and a recognized risk of severe intoxication. Interpretation of postmortem drug concentrations is complicated by postmortem redistribution (PMR), yet systematic toxicokinetic and multi-tissue PMR data for amantadine remain limited.

An integrated investigation of amantadine toxicokinetics and postmortem redistribution was conducted in male rats. For toxicokinetic assessment, a single oral dose of 450 mg/kg (LD50) was administered, and concentrations were quantified in blood and nine tissues over a 96-h period. For the PMR study, rats received low (42 mg/kg), medium (LD50), and high (2 × LD50) doses, followed by controlled postmortem storage at 4 °C and 20 °C for up to 96 h. Amantadine concentrations were determined using validated HPLC–MS/MS methods and analyzed by pharmacokinetic and statistical approaches.

Amantadine was rapidly absorbed and widely distributed, exhibiting pronounced tissue-specific heterogeneity. The liver and kidney showed the highest exposure, whereas accumulation in the brain and testis was limited. Postmortem redistribution was substantial and tissue dependent, and was strongly influenced by dose, postmortem interval, and storage temperature. Blood concentrations were unstable over time, while solid organs, particularly the liver and spleen, exhibited higher and more sustained postmortem concentrations. Notably, selected inter-tissue concentration ratios (e.g., liver-to-lower limb muscle and spleen-to-brain) displayed consistent, dose-dependent trends across postmortem conditions.

This study provides a comprehensive characterization of amantadine toxicokinetics and postmortem redistribution across multiple biological matrices. The findings underscore the limitations of relying solely on postmortem blood concentrations and support the complementary use of selected tissues and inter-tissue concentration ratios as comparative indicators in toxicological interpretation. These results offer mechanistic insight into postmortem drug dynamics and provide practical reference data to improve the interpretation of suspected amantadine intoxication.

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