Distribution of Eight QT-Prolonging Drugs and Their Main Metabolites Between Postmortem Cardiac Tissue and Blood Reveals Potential Pitfalls in Toxicological Interpretation

Abstract

Femoral blood concentrations are usually used in postmortem toxicology to assess possible toxic effects of drugs. This includes QT-prolongation and other cardiac dysrhythmia, which could have been the cause of death. However, blood concentration is only a surrogate for the active site concentration, and therefore cardiac tissue concentration may provide a more accurate toxicological interpretation. Thus, cardiac tissue and femoral and cardiac blood concentrations were examined for eight frequently used QT-prolonging drugs (QTD) and their metabolites in a mentally ill population. In total, 180 cases were included from the Danish autopsy-based forensic study SURVIVE. The concentrations were analyzed using ultra-performance liquid chromatography coupled with tandem mass spectrometry utilizing stable isotopically labeled internal standards. The results showed that the cardiac tissue concentrations were significantly higher compared to femoral and cardiac blood concentrations, with two exceptions. The median cardiac tissue-to-femoral blood concentration ratio (Kb) ranged from 2.2 (venlafaxine) to 15 (nortriptyline). The inter-individual fold difference between the minimum and maximum Kb ranged from 2.6-fold (Z-hydroxynortriptyline) to 61 (venlafaxine). For 12 compounds, postmortem redistribution appeared to be minimal, whereas four compounds displayed some degree of postmortem redistribution. Citalopram and quetiapine were selected for in-depth analysis of the relation between the toxicological interpretation and femoral blood/cardiac tissue concentrations. Within this dataset, citalopram displayed a wide overlap in cardiac tissue concentrations (~50%) between non-toxic and toxic citalopram cases, as estimated from femoral blood concentrations. In contrast, quetiapine displayed no overlap in cardiac tissue concentrations between non-toxic and toxic quetiapine cases based on femoral blood concentrations. The implication of the citalopram finding is that possible intoxications can be overlooked when only considering femoral blood concentrations. Based on the present findings, non-toxic cardiac tissue 10th-90th percentile concentration ranges were estimated for citalopram (0.93-4.4 mg/kg) and quetiapine (0.0073-0.60 mg/kg).

Methadone Blockade of Cardiac Inward Rectifier K + Current Augments Membrane Instability and Amplifies U Waves on Surface ECGs: A Translational Study

“…Published values of the maxium concentration for methadone in patients undergoing opioid replacement therapy are 5‐ to 10‐fold lower than the IC 50 for suppression of I K1 and I Kr as reported here; however, cardiac tissue levels of methadone may be significantly higher than measured blood levels. 30 Indeed, we observed QT prolongation in patients following methadone induction, indicative of significant suppression of I Kr , and likely I K1 as well. However, we observed no cardiac arrhythmias or arrest in patients involved in the study.…”

“…Serum values may be unreliable indicators of myocyte receptor interactions, however. Directly measured cardiac concentrations of methadone averaged 4.7‐fold higher than serum concentrations at autopsy, 30 and therefore appear comparable to the IC 50 for suppression of I K1 . These data suggest that ordinary use of methadone will often result in substantial inhibition of I K1 .…”

Suitability of cardiac blood, brain tissue, and muscle tissue as alternative matrices for toxicological evaluation in postmortem cases

“…This indicates that if the concentration in blood increases, the concentration in the alternative matrix also increases. Opioids are some of the most studied analytes in paired samples of peripheral blood and alternative matrices in the literature, where their concentration ratios in brain tissue, 21,27,32,35,[39][40][41] cardiac blood, [8][9][10]12,16,[40][41][42][43] and muscle tissue relative to peripheral blood 10,23,[40][41][42][44][45][46] are either reported or can be calculated from the concentrations. Even though some of the studies include many cases, there is a lack of consensus in the concentration ratios reported, with wide ranges generally being observed and the mean and median differing between studies.…”

Antipsychotics in routine treatment are minor contributors to QT prolongation compared to genetics and age

“…The affinity of psychotropic drugs towards cardiac ion channels is lower than their affinity towards their primary pharmacological targets such as the dopamine D 2 - or the serotonin 5-HT 2A- receptor and the K d of ion channel inhibition is above the therapeutic range ( Abi-Gerges et al, 2011 ; Hiemke et al, 2018 ; Silvestre et al, 2014 ). Nevertheless, due to accumulation of drugs in cardiac tissues leading to locally toxic concentrations or accidental intoxication, QT prolongation is feasible even under therapeutic drug concentrations ( Mikkelsen et al, 2018 ). However, clinical studies on this topic showed inconsistent results.…”