Estimation of Cyanide Ingestion Time Using Metabolite Concentration Ratios and Regression Modeling Based on Toxicokinetic Data in Rabbits

Abstract

Background: Determining the time of cyanide exposure is critical in forensic and clinical practice. Aims and Objectives: This study characterized the toxicokinetics of cyanide (CN⁻) and its metabolites (2-amino-2-thiazoline-4-carboxylic acid [ATCA] and SCN⁻) following oral administration to develop mathematical models based on metabolite ratios for estimating the time since ingestion. Materials and Methods: An animal model was established using rabbits orally dosed with potassium cyanide. Serial blood samples were collected over 24 h, with concentrations of CN⁻, ATCA, and SCN ⁻ quantified through chromatographic techniques (gas chromatography-electron capture detector, liquid chromatography–tandem mass spectrometry, and ion chromatography). Pharmacokinetic parameters were derived using noncompartmental analysis based on statistical moment theory. Results: Cyanide demonstrated rapid absorption kinetics, achieving peak concentration (Cₘₐₓ =1.29 ng/μL) at 0.75 h postadministration. Metabolite formation showed distinct delays, with ATCA and SCN ⁻ reaching maximum levels at 3 h and 6 h, respectively. Elimination kinetics revealed SCN ⁻ had significantly prolonged clearance compared to ATCA. Regression models developed for metabolite ratios (ATCA/SCN⁻, ATCA/CN⁻, SCN⁻/CN⁻) all exhibited excellent correlation with time ( R ² >0.98). The ATCA/SCN ⁻ ratio model demonstrated particular utility, maintaining prediction accuracy within 20% of actual values throughout the 12-h postingestion period. Conclusions: This study successfully established the temporal patterns of cyanide metabolism and elimination. The developed ATCA/SCN ⁻ ratio model provides a validated approach for estimating cyanide exposure time, offering substantial practical value for forensic investigations and clinical toxicology applications.