A Study of 11-[³H]-Tetrodotoxin Absorption, Distribution, Metabolism and Excretion (ADME) in Adult Sprague-Dawley Rats.

Bihong Hong,Ruizao Yi,Yanming Dong,Kaikai Bai,Quanling Xie,Hui Chen,Jiacai Han,Jianlin He

doi:10.3390/md15060159

Abstract

Tetrodotoxin (TTX) is a powerful sodium channel blocker that in low doses can safely relieve severe pain. Studying the absorption, distribution, metabolism and excretion (ADME) of TTX is challenging given the extremely low lethal dose. We conducted radiolabeled ADME studies in Sprague-Dawley rats. After a single dose of 6 μg/(16 μCi/kg) 11-[3H]TTX, pharmacokinetics of plasma total radioactivity were similar in male and female rats. Maximum radioactivity (5.56 ng Eq./mL) was reached in 10 min. [3H]TTX was below detection in plasma after 24 h. The area under the curve from 0 to 8 h was 5.89 h·ng Eq./mL; mean residence time was 1.62 h and t½ was 2.31 h. Bile secretion accounted for 0.43% and approximately 51% of the dose was recovered in the urine, the predominant route of elimination. Approximately 69% was recovered, suggesting that hydrogen tritium exchange in rats produced tritiated water excreted in breath and saliva. Average total radioactivity in the stomach, lungs, kidney and intestines was higher than plasma concentrations. Metabolite analysis of plasma, urine and feces samples demonstrated oxidized TTX, the only identified metabolite. In conclusion, TTX was rapidly absorbed and excreted in rats, a standard preclinical model used to guide the design of clinical trials.

Highlights

Tetrodotoxin (TTX) is a potent neurotoxin found in a variety of marine and terrestrial species [1,2,3,4,5,6,7,8].Clinical studies suggest that low doses of TTX can safely relieve severe cancer-related pain [9,10,11]and reduce cue-induced drug craving and anxiety in abstinent heroin addicts [12]
No paradoxical reactions were observed during the experiments after a single intramuscular dose of 6 μg/(16 μCi/kg) 11-[3 H]TTX in male or female rats
In addition to the liquid chromatography (LC)-mass spectrometry (MS)/MS, mass defect filtration products of TTX in phase I and II in the urine samples and the results showed no mass peak of TTX

Summary

Introduction

Tetrodotoxin (TTX) is a potent neurotoxin found in a variety of marine and terrestrial species [1,2,3,4,5,6,7,8].Clinical studies suggest that low doses of TTX can safely relieve severe cancer-related pain [9,10,11]and reduce cue-induced drug craving and anxiety in abstinent heroin addicts [12]. Clinical studies suggest that low doses of TTX can safely relieve severe cancer-related pain [9,10,11]. TTX is a powerful sodium channel blocker [13] and the median lethal dose (LD50 ) is about 10 μg/kg for adult. The amount of TTX in the blood, urine and tissues is extremely low, as well as its metabolites. Both are very polar compounds, which may cause the problem of ion suppression in mass spectrometry (MS) analysis. Liquid chromatography-mass spectrometry (LC-MS) and especially LC-MS/MS are regarded as the most popular and sensitive methods for determination of TTX in plasma and urine [14]. Jen et al [15] used solid-phase extraction combined with LC-MS/MS

Objectives

Methods

Results

Discussion

Conclusion