Isoform-specific Modulation of Drug Metabolism in a Fatality Involving Olanzapine Overexposure: Inflammation-Induced Phenoconversion as a Mechanistic Framework

BACKGROUND: Interindividual variability influences adverse drug reactions and unexpected drug-related deaths. Despite increasing pharmacogenetics incorporation in clinical practice, acquired metabolic activity modifiers remain insufficiently integrated into toxicological interpretation. Here, the authors report an olanzapine overexposure fatality occurring despite therapeutic dosing, highlighting isoform-specific inflammation-induced phenoconversion. METHODS: A medico-legal investigation (including review of the medical file, full autopsy, toxicological [femoral blood and urine], and pharmacogenetic analyses [CYP1A2/2D6/2C8/2C9 and UGT1A4 genes]) was conducted in a 57-year-old woman hospitalized for bipolar disorder with psychotic features. She was administered titrated therapeutic does of olanzapine. RESULTS: The investigation indicated an acute systemic inflammatory state, characterized by neutrophilic leukocytosis (16 × 109/L) and elevated C-reactive protein (62 mg/L). A toxic femoral blood olanzapine concentration (172 mcg/L) and CYP1A2*30/*30, CYP2C8*1/*3, CYP2D*62/*5, and UGT1A4*1B/*1 genotypes were revealed by the toxicological and pharmacogenetics analyses, respectively. None of which alone accounted for the observed olanzapine accumulation. CONCLUSIONS: The selective accumulation of olanzapine, contrasted with preserved exposure to drugs predominantly metabolized by CYP3A4/2D6/alternative UGT isoforms, supports isoform-specific metabolic inhibition. CYP1A2 was the most plausible target of suppression. Although the impact of inflammation on UGT activity is less well characterized and appears isoform- and substrate-dependent, the selective modulation of UGT1A4 cannot be excluded. Overall, this case emphasizes that inflammation may differentially affect metabolic isoenzymes, and that both cytochrome P450- and UGT-mediated pathways should be considered when interpreting unexpected psychotropic drug overexposure.