Postmortem redistribution and degradation of dothiepin. Human case studies and an animal model

Two suicides took estimated maximum dothiepin doses of 765 and 1875 mg, respectively. Initial drug levels in nine and 12 blood samples were 0.26-1.85 and 4.08-23.98 mg/L, with highest concentrations in the pulmonary veins. Pulmonary artery concentrations rose markedly over 18 h: 0.32 rising to 0.9, and 6.54 rising to 19.53 mg/L. Peripheral blood concentrations were relatively stable. Concentrations in liver, heart, lung, and skeletal muscle were, for case 1, 4.3, 2.92, 18.6, and 1.1 mg/kg; and, for case 2, 52, 16.8, 73.9, and 8.98 mg/kg. New Zealand white female rabbits (2.4-3.2 kg) given 20 mg dothiepin hydrochloride intravenously were killed with pentobarbital after 1 h. Blood was sampled from the thorax, infra-renal inferior vena cava, and supra-renal inferior vena cava at 0, 1/2, 1, 4, 8, 12, and 24 h postmortem in paired animals. Liver, heart, lung, and skeletal muscle were sampled at 0 and 24 h. Mean dothiepin levels in thoracic blood rose from 0.43 mg/L at time 0 to 1.73 at 8 h and then fell to 0.61 at 12 h, likely reflecting initial redistribution from the lungs (63.4 mg/kg at time 0 and 27.3 mg/kg at 24 h) followed by putrefaction-associated bacterial degradation. Falls in blood drug levels associated with putrefaction were not seen in the human cases. Interpretation of postmortem dothiepin blood concentrations is complicated by pronounced interindividual variations in in vivo pharmacokinetics, the postmortem redistribution phenomenon, and variable drug degradation by bacteria.