Metabolic and Pharmacokinetic Profiling Studies of N, N-Dimethylaniline-Heliamine in Rats by UHPLC-Q-Orbitrap MS/MS
Ruqi Xi1,2, Rahima Abdulla1, Jurakulov Sherzod3
1State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, CAS Key Laboratory of Chemistry of Plant Resources in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China.
Insights
N, N-dimethylaniline-heliamine (DH), a synthetic antiarrhythmic, was studied for its metabolism and pharmacokinetics in rats. Researchers identified 16 metabolites and found DH has low toxicity and appropriate oral bioavailability.
Area of Science:
- Pharmacology and Toxicology
- Drug Metabolism and Pharmacokinetics
Background:
- Cardiovascular disease is the leading global cause of death.
- N, N-dimethylaniline-heliamine (DH), a synthetic tetrahydroisoquinoline alkaloid, exhibits antiarrhythmic properties.
- Metabolic and pharmacokinetic profiles of DH in rats remain uncharacterized.
Purpose of the Study:
- To identify DH metabolites in rats using in silico, in vitro, and in vivo approaches.
- To develop and validate a bioanalytical method for quantifying DH in rat plasma.
- To determine the pharmacokinetic characteristics and oral bioavailability of DH in rats.
Main Methods:
- Metabolite identification via in silico, in vitro, and in vivo studies.
- Development and validation of a sensitive bioanalytical method for DH quantification in plasma.
- Non-compartmental analysis of plasma concentration-time data to determine pharmacokinetic parameters.
Main Results:
- Sixteen DH metabolites were identified (12 Phase I, 4 Phase II), with major metabolic pathways including demethylation, dehydrogenation, glucuronidation, and sulfation.
- In silico analysis predicted a low probability of DH binding to DNA, protein, and glutathione.
- Pharmacokinetic analysis revealed a volume of distribution of 126,728.09 ± 56,867.09 mL/kg, clearance of 30,148.65 ± 15,354.27 mL/h/kg, and absolute oral bioavailability of 16.11%.
Conclusions:
- DH is extensively metabolized in rats through various pathways.
- The high volume of distribution suggests significant tissue distribution of DH in rats.
- DH demonstrates appropriate oral bioavailability, diverse excretion routes, and low toxicity, supporting its potential as an antiarrhythmic agent.
Abstract:
Cardiovascular disease is the first cause of death worldwide and kills more people each year than any other cause of death. N, N-dimethylaniline-heliamine (DH), a synthetic tetrahydroisoquinoline alkaloid, has shown notable antiarrhythmic activity. However, the metabolic processes and pharmacokinetic characteristics of DH in rats have not been studied. This study aims to identify its metabolites, as well as develop and validate a rapid and efficient bioanalytical method for quantifying DH in rat plasma over a wide range of concentrations. Its metabolites were characterized in silico, in vitro, and in vivo. A series of 16 metabolites were identified, of which 12 were phase I metabolites and 4 were phase II metabolites. A low probability of DH binding to DNA, protein, and glutathione is predicted by the in silico model. The main metabolic processes of DH were demethylation, dehydrogenation, glucuronidation, and sulfation. Concentration-time profiles were generated by analyzing the plasma, and the outcomes were analyzed via non-compartmental analysis to identify the pharmacokinetic parameters. Among the detected parameters were the volume of distribution, estimated at 126,728.09 ± 56,867.09 mL/kg, clearance at 30,148.65 ± 15,354.27 mL/h/kg, and absolute oral bioavailability at 16.11%. The plasma distribution volume of DH was substantially higher than the overall plasma volume of rats, which suggests that DH has a specific tissue distribution in rats. This study suggests that DH is appropriately bioavailable and excreted via a variety of routes and has low toxicity.
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