Postmortem distribution of isotonitazene and its three metabolites in the first lethal case observed in France

Isotonitazene (IZN) is a potent synthetic opioid associated with a growing number of fatal intoxications worldwide. Despite its increasing presence in forensic cases, postmortem data regarding the distribution of IZN and its metabolites in human tissues remain limited.

We report the first documented case of fatal IZN intoxication in France, involving a 39-year-old man with a history of heroin use. Comprehensive postmortem toxicological analysis was conducted using a LC-MS/MS quantification method. Quantification of IZN and its three active metabolites: N-desethyl-isotonitazene, 4'hydroxy-nitazene, and 5-amino-isotonitazene was performed in multiple matrices, including blood, urine, bile, and solid organs.

IZN was detected in femoral and cardiac blood, with concentrations of 1.20 ng/mL and 1.74 ng/mL, respectively. High concentrations were observed in the heart (20 ng/g), lungs (32.6 ng/g), and brain (7.9 ng/g), consistent with marked postmortem redistribution. Active metabolites showed variable distribution: N-desethyl isotonitazene was detected in lung tissue and brain, 5-amino isotonitazene in both brain and lungs, while 4'-hydroxy-nitazene appeared to be predominantly eliminated via the biliary route. A high concentration of IZN at the injection site (343.2 ng/mL) indicated intravenous administration. Ethanol and cetirizine were also present at non-lethal concentrations.

To the best of our knowledge, this is the first reported fatal IZN intoxication with comprehensive postmortem analysis, including quantification of active metabolites in solid organs. The case is marked by low peripheral blood levels, extensive redistribution, and selective tissue accumulation. Active metabolites: N-desethyl IZN, 4'-hydroxy-nitazene, and 5-amino IZN showed distinct distribution and elimination profiles. These findings highlight the high potency, rapid metabolism, and complex toxicokinetic of IZN.