Preclinical Pharmacokinetics Study of a Novel Intravenous Anesthetic ET-26 Hydrochloride

Background: ET-26 hydrochloride is a novel intravenous anesthetic, approved for clinical trials, that produces a desirable sedative-hypnotic effect with stable myocardial performance and mild adrenocortical suppression in rats and beagle dogs. The objective of this study was to assess the absorption, distribution, metabolism, and excretion of ET-26 hydrochloride. Methods: Hepatocytes from human, monkey, dog, rat, and mouse were used to determine the metabolites of ET-26 hydrochloride. Distribution and excretion were assessed in rats and pharmacokinetic studies were performed in beagle dogs. Results: The metabolic pathway and proposed structure of metabolites were fully assessed resulting from the biotransformation reactions of hydrolysis, dehydrogenation, demethylation and glucuronic acid conjugation. The main distribution of the drug was in fat (15067 ± 801 ng/ml) and liver (13647 ± 1126 ng/ml), and the kidney was the primary excretion route (4.47%-11.94%). The Cmax after injection with 1.045 mg/kg, 2.09 mg/kg, and 4.18 mg/kg was 1476.5 ± 138.9 ng/ml, 2846.1 ± 223.3 ng/ml, and 6233.3 ± 238.9 ng/ml, respectively. The t1/2 of the drug was similar across dose groups at 74.8 ± 10.8 min to 81.4 ± 4.2 min. The AUC0-t values were 30208.1 ± 2026.5 min*ng/ml, 62712.8 ± 1808.3 min*ng/ml, and 130465.2 ± 7457.4 min*ng/ml, respectively. Conclusion: The metabolic pathway and the proposed structure of metabolites for ET-26 hydrochloride were fully assessed. The majority of distribution for ET-26 hydrochloride occurs in the fat and liver, while the primary route of excretion for ET-26 hydrochloride is through the kidney. In dogs, pharmacokinetic features of ET-26 hydrochloride had a linear relationship with dosage.