Postmortem Drug Concentrations Research Articles

Comparative analysis of post-mortem drug concentrations in cerebrospinal fluid and blood.

This study aimed to compare the concentration of various xenobiotics in both cerebrospinal fluid (CSF) and blood. We examined 175 autopsy cases covering a wide range of ages, causes of death, and drug ingestion histories, with cerebrospinal fluid and blood samples available for toxicological testing. Analytes studied included opioids, benzodiazepines, antidepressants, antipsychotics, and illicit substances such as cannabinoids, stimulants and new psychoactive substances, including synthetic cathinones and synthetic cannabinoids. We found that concentrations in CSF were generally lower than in blood. A significant correlation was observed between drug concentrations in CSF and blood for many analytes (p < 0.05). However, the strength and direction of the correlation varied considerably depending on the physicochemical properties of the drugs, suggesting that a 'one size fits all' model may not be applicable. The results indicate that cerebrospinal fluid (CSF) can be used to detect a variety of xenobiotics, particularly amphetamines, synthetic cathinones and synthetic cannabinoids, in cases where conventional biological materials are not available. Additionally, using the results obtained in the future can lead to a better understanding of pharmacokinetic processes and the effect of post-mortem redistribution. Further research is needed to refine our understanding of these relationships.

Postmortem redistribution of amphetamines and benzodiazepines in humans: Important variables that might be influencing the central blood / peripheral blood ratio

IntroductionThe primary objective of postmortem forensic toxicology is to determine if toxicological substances detected in bodily material of victims have contributed to the death of the victim. Interpretation of postmortem drug concentrations is hindered by the fact that time and site dependent variations in postmortem drug concentrations occur, as a result of postmortem redistribution (PMR). An often-used marker for the occurrence of PMR, is the cardiac blood concentration/peripheral blood concentration ratio (C/P ratio) of a drug. In this study, we investigated the relationship between 13 variables and the C/P ratios of amphetamines and benzodiazepines. MethodToxicological results of all postmortem cases that were positive for amphetamines (amphetamine, MDMA, MDA) and/or benzodiazepines (diazepam, desmethyldiazepam, temazepam, oxazepam, midazolam, α-hydroxymidazolam) investigated by the Netherlands Forensic Institute between January 1 2010 and July 31 2020 were reviewed. A total of 112 amphetamine positive cases (224 paired specimen) and 179 benzodiazepine positive cases (358 paired specimen) were selected. The C/P ratios were determined for all selected cases. Ratios were compared between subgroups by performing either a Mann-Whitney U test or a Kruskal-Wallis test followed by post-hoc Mann-Whitney U test. ResultsAfter dividing cases in quartiles based on their amphetamine concentration in femoral blood, the amphetamine C/P ratio was significantly lower in cases with a high amphetamine concentration (quartile 4) compared to cases with a low amphetamine concentration (quartiles 1 and 2) with median C/P ratios of 1.6, 2.4 and 2.2, respectively (p-value<0.001 and p-value=0.001, respectively).The MDA C/P ratio was significantly higher in cases where trauma was the cause of death compared to cases where intoxication was the cause of death with median C/P ratios of 3.3 and 1.6, respectively (p-value<0.001). The MDA C/P ratio was also significantly lower in cases where resuscitation was attempted compared to cases where no resuscitation was attempted with median C/P ratios of 1.6 and 2.4, respectively (p-value=0.003). However, a significant dependency between the variables cause of death and attempted resuscitation was observed.No significant differences in benzodiazepine C/P ratios were observed between subgroups of any of the investigated variables. However, the low p-value of BMI suggests a potential difference in midazolam C/P ratio between BMI subgroups (p-value=0.027). ConclusionWhen interpreting postmortem toxicological results, it might prove useful to take the above-mentioned variables into account.

Postmortem redistribution of drugs: a literature review.

Postmortem drug analysis is crucial in identifying the potential cause and manner of death. However, it is threatened by a significant phenomenon called postmortem redistribution (PMR), which refers to the alterations in drug levels occurring after death. This review aims to describe the PMR phenomenon, the mechanisms involved in the PMR of drugs, the various methods used to predict it, and various artifacts of postmortem drug concentrations. Several mechanisms, including passive diffusion from solid organs that act as drug reservoirs to the surrounding tissues, cadaveric changes after death (e.g., cell death, blood coagulation, hypostasis, and movements), and the putrefactive process, can result in artifacts of postmortem drug concentrations. The drug's chemical and pharmacokinetic properties (such as acidic/basic properties, lipophilicity, protein binding, high volume of distribution, and residual metabolic activity) are additional factors. Several markers, including cardiac blood-to-peripheral blood ratio (C/P), liver-to-peripheral blood ratio (L/P), amino acid markers such as methionine, quantitative structure-activity relationship (QSAR) approach, and F factor, have been proposed for interpreting the liability of drugs to PMR. Several artifacts may affect the reliability of postmortem drug analysis. Peripheral blood is preferred for postmortem drug sample collection. Numerous laboratories evaluate the redistribution potential of drugs after death using the C/P concentration ratio. Nevertheless, the L/P concentration ratio is proposed to be a more reliable marker for PMR determination.

Fatal concentrations of antidepressant and antipsychotic drugs in post-mortem femoral blood.

Antidepressants and antipsychotics are both an important class of prescription drugs within post-mortem (PM) toxicology because most of the substances are toxic in overdose and the mental disorders being treated may be associated with suicidality. A wide range of antidepressants and antipsychotics are currently included in up-to-date PM toxicology analysis protocols. However, apart from case studies, few reports on fatal concentrations based on large number of cases have been published in the literature. Based on PM investigations in Finland between 2000-2020, this study provides fatal reference concentrations in poisonings due to an antidepressant or an antipsychotic drug assigned as the principal intoxicant. Summary statistics for drug concentrations in PM femoral blood (min, max, mean, 10th, 25th, 50th, 75th, 90thpercentile) were calculated for 17 antidepressant (N = 2007) and for 12 antipsychotic drugs (N = 1161). The proportion of suicide, accident and undetermined manner of death is indicated for each drug. Further, the fatal concentrations obtained in this study were evaluated by comparison with fatal and "normal" PM concentrations reported by two previously published approaches, the grouped causes of death approach and the all causes of death approach, respectively. This study shows that, despite the well-known variation in PM drug concentrations, competently generated fatal concentration results for the drugs studied are consistent to such an extent that they can be used as a reference in the interpretation process.

Postmortem redistribution of cocaine and its metabolites, benzoylecgonine and ecgonine methyl ester in humans: Important variables that might be influencing the central blood / peripheral blood ratio

IntroductionA big challenge in forensic toxicology is the correct interpretation of the results of quantitative analyses in postmortem cases. Postmortem drug concentrations not necessarily reflect the drug concentrations at the time of death, due to postmortem changes in drug concentrations caused by postmortem redistribution (PMR). Cardiac blood is more prone to PMR related concentration changes than peripheral blood. Because of this difference in susceptibility to PMR related concentration changes, the ratio of cardiac blood concentration/peripheral blood concentration (C/P) of a drug is an often-used marker of PMR. In this study, we investigated the relationship between different potentially significant variables and the C/P ratios of cocaine, benzoylecgonine (BE) and ecgonine methyl ester (EME) in humans. The aim was to elucidate the mechanisms involved in PMR of these substances and potentially provide guidelines aiding forensic toxicologists in the interpretation of postmortem quantitative results of cocaine and its metabolites. To differentiate between postmortem concentration changes due to redistribution versus degradation of cocaine, the relationships between these variables and metabolite/cocaine ratios were investigated as well. MethodToxicological results of all postmortem cases that were positive for cocaine, BE and/or EME investigated by the Netherlands Forensic Institute between January 1st 2010 and July 31st 2020 were reviewed. The C/P ratios, BE/cocaine ratios and EME/cocaine ratios were determined for all selected cases. Cocaine, BE and/or EME were quantified in both femoral blood and cardiac blood in a total of 148 cases. Ratios were compared between subgroups by performing either a Mann-Whitney U test or a Kruskal-Wallis test followed by post-hoc Mann-Whitney U test. ResultsA statistically significant difference in C/P ratio of EME was observed between trauma and non-trauma cases with median C/P ratios of 2.03 and 1.57, respectively (p value=0.001). A statistically significant difference in EME/cocaine ratio was observed between the BMI subgroups 18.5 – 25.0 kg/m2 and> 25 kg/m2 with median EME/cocaine ratios of 3.79 and 1.58, respectively (p-value<0.001). ConclusionPostmortem cocaine concentrations should be interpreted with caution, considering the occurrence of both PMR and postmortem degradation. When interpreting postmortem toxicological results in cocaine-related fatalities, it might prove useful to take the above-mentioned variables into account.

Postmortem drug concentrations in forensic pharmacology

ABSTRACT Forensic pharmacology involves interpreting the concentration of a drug or toxin found in the dead body in relationship to premortem events. Immediately after death, the concentrations of practically all drugs will be subject to multiple processes resulting in drug redistribution. Interpretation of a specific post-mortem result requires the integration of many independent and interacting antemortem, mortem and post-mortem factors. The consequences can be as far reaching as conviction or exoneration from the charge of murder.

Fatal concentrations of antidepressants and antipsychotics in post-mortem blood

The objective was to compare the summary statistics for fatal antidepressant and antipsychotic drug concentrations mined by different approaches from post-mortem (PM) toxicological data. Reference concentrations of drugs play a major part in the interpretation of PM toxicology results. However, PM drug concentrations are not necessarily the same as those at the time of death, and consequently standard tables of clinical plasma concentration data are of limited value. Compilations of PM concentrations collected from literature sources are often heterogeneous in terms of the sampling site, the analytical methods used, and the number of cases involved. However, there are also published summary statistics for drug concentrations in PM femoral venous blood, based on extensive databases from centralized laboratories with well-established and high-quality working practices. The present study establishes concentration distributions for a number of antidepressant and antipsychotic drugs, specified as a principal finding in fatal poisoning (principal finding approach). These levels are then compared with those obtained using two previous approaches: according to the all-causes-of-death (Ketola RA, Drug Test Anal, 2019, 11, 1326–1337) or according to the grouped causes of death, aka “the Druid approach”, where the reference information is subdivided into poisonings by one specific substance only, multi-substance poisonings and non-poisoning controls (Reis M, J Anal Toxicol, 2007, 31, 254-264; Söderberg C, Forensic Sci Int, 2016, 266, 91-101). Summary statistics for fatal antidepressant and antipsychotic drug concentrations in PM femoral venous blood were generated according to the principal drug finding. In most cases, also other drugs were implicated in the cause of death. The data were mined between 2000–2020 from the national PM toxicology database, maintained by the Finnish Institute for Health and Welfare, in which all results of the toxicological analyses in medico-legal investigations and information from the respective death certificates are collected. From this material, those antidepressant and antipsychotic drugs that had been quantitatively analysed at least 10 times were selected. Concentration percentiles (10th, 50th, 90th, 95th, 97.5th) were calculated for 16 different antidepressant ( N = 1999) and for 7 different antipsychotic drugs ( N = 1134), defined as principal findings of fatal poisoning by forensic pathologists. For instance, for the antidepressant amitriptyline the respective concentrations were 0.66, 2.0, 8.3, 13 and 25 mg/L, and for the antipsychotic levomepromazine (methotrimeprazine) 0.40, 1.5, 5.3, 10 and 16 mg/L. A comparison with other data mining approaches will be presented in visual form. A clear correspondence was found between, for example, the 90th percentile concentration level of the present principal finding approach and the 97.5th percentile concentration level of the all-causes-of-death approach. Similarly, a correspondence was found between, for example, the median concentration level of the present principal finding approach and the median concentration level of the multi-substance poisoning group in the Druid approach. The novel data presented in this study followed by a systematic comparison with data from previous studies helps rationalize the use of reference concentrations from various sources in the interpretation of potential poisoning deaths. Further data mining for additional drugs will be markedly easier in the principal finding approach than in the Druid approach, provided that the principal findings are specified in advance in the database as is in our case. Despite the proven usefulness of reference concentrations, interpretation must always be made on a case-by-case basis, taking into account e.g. background information, autopsy findings, and substance interactions. A forensic toxicologist must have the evidence-based PM concentration information at his or her disposal when assisting a forensic pathologist in determining the cause of death or being called to testify in court.

Just say no to postmortem drug dose calculations.

For years, a number of professional groups have warned forensic and clinical toxicologists against calculating an administered dose of a drug based on postmortem blood drug concentrations. But to date, there has been limited information as to how unreliable these dose calculations may actually be. Using amitriptyline as a model drug, this study used empirically determined pharmacokinetic variables for amitriptyline from clinical studies coupled with clinical overdoses (where the individual survived), and death case studies (ascribed to amitriptyline toxicity) in which the dose of amitriptyline was known. Using these data, standard pharmacokinetic equations, and general error propagation, it was possible to estimate the accuracy of calculated doses of amitriptyline, compared with the doses that were consumed. As was expected in postmortem cases, depending on the pharmacokinetic equation used, the accuracy (mean +128% to +2347%) and precision (SD±383% to 3698%) were too large to allow reliable estimations of the dose of amitriptyline consumed prior to death based on postmortem blood drug concentrations. This work again reinforces that dose calculations from postmortem blood drug concentrations are unreliable.

Pediatric opioid fatalities: What can we learn for prevention?

The aim of this study was to highlight 19 cases investigated by the North Carolina Office of the Chief Medical Examiner over the last 12years involving accidental or undetermined manner of death opioid ingestions leading to fatalities in young children. These pediatric ingestions have closely mirrored the opioid epidemic in adults transitioning from prescription medications to illicit drugs including fentanyl and fentanyl analogues. Unlike a typical adult ingestion for purposes of self-harm or pleasure, poisonings in toddlers and infants are usually the result of curiosity, exploration, a decreased sense of danger, or imitation of adult or older sibling behavior. Eleven of the decedents were between the ages of 8 and 24months. Among the cases were 12 prescription opioid exposure deaths and 7 illicit drug poisonings. A majority of the decedents were found unresponsive in an unkept home and/or in unsafe sleeping spaces with easy access to drugs or drug materials, which stresses the importance of safe pediatric sleeping conditions. After a complete pathological investigation, several of the cases had physical or scene evidence demonstrating that foil, plastic, or paper small enough to be ingested can contain enough potent opioid to cause death. Details from the toxicological investigation are included for each case to provide postmortem whole blood drug concentrations for forensic practitioners. Accidental pediatric poisonings are preventable. Risk reduction through improving awareness and education of the dangers of opioids is a key factor in mitigating these tragedies.

Postmortem Drug Redistribution: A Compilation of Postmortem/Antemortem Drug Concentration Ratios.

Postmortem drug redistribution (PMR) is a well-known phenomenon in forensic toxicology with implications for medico-legal death investigations. Paired antemortem (AM) specimen and postmortem (PM) mortuary admission femoral blood drug concentrations from 811 coronial cases were used to construct a retrospective compilation of PM/AM drug concentration ratios for 42 parent drugs and metabolites. The median PM/AM ratios for all antidepressants were > 1 and consistent with PMR In contrast, the median PM/AM ratios of most benzodiazepines were < 1. The antipsychotics were varied (0.63-3.3) and suggest the mixed effects of PMR and drug instability. Amphetamines exhibited no trends (0.90-0.95) and are likely confounded by many factors. The PM/AM ratios of cardiovascular drugs, opioids and other drugs are also reported. This research represents an expansive retrospective compilation of paired AM and PM drug concentrations for many toxicologically relevant drugs. While the median PM/AM ratios demonstrate some drug-dependent trends, there was no obvious relationship between AM specimens and PM femoral blood taken at mortuary admission.

Postmortem metabolomics: Correlating time-dependent concentration changes of xenobiotic and endogenous compounds.

Postmortem redistribution (PMR) describes the artificial postmortem concentration changes of xenobiotics that may pose major challenges in forensic toxicology. Only a few studies have systematically investigated time-dependent postmortem drug concentration changes so far and the a posteriori estimation of the occurrence of PMR is not yet possible. In this context, the general concept that postmortem biochemical changes in blood might parallel drug redistribution mechanisms seems promising. Thus, the current study investigated the possible correlations between time-dependent postmortem concentration changes of xenobiotic and endogenous compounds; exemplified for authentic morphine (n = 19) and methadone (n = 11) cases. Peripheral blood samples at two time-points postmortem were analyzed for morphine and methadone concentrations and an (un)targeted postmortem metabolomics approach was utilized to combine targeted quantitative analysis of 56 endogenous analytes and untargeted screening for endogenous compounds (characterizing 1174 features); liquid and gas chromatography-mass spectrometry was used respectively. Individual statistically significant correlations between morphine/methadone and endogenous compounds/features could be determined. Hence, the general applicability of the proposed concept could successfully be confirmed. To verify the reproducibility and robustness of the correlating behavior, a larger dataset must be analyzed next. Once a marker/set of markers is found (e.g. robust correlation with specific xenobiotic or xenobiotic class), these could be used as surrogates to further study the time-dependent PMR in a broader variety of cases (e.g. independent of a xenobiotic drug present). A crucial next step will also be the attempt to create a statistical model that allows a posteriori estimation of PMR occurrence of xenobiotics to assist forensic toxicologists in postmortem case interpretation.

The importance of sample size with regard to the robustness of postmortem reference values

Evaluating postmortem toxicological results is a challenging task due to multiple factors affecting blood concentrations after death. In order to improve the diagnostic accuracy in cases of suspected fatal intoxication different compilations of postmortem reference drug concentrations are often used. However, it is not clear what constitutes a reliable postmortem reference value.The current study presents reference concentrations for 13 substances from seven substance groups according to a standardized protocol. The reference concentrations were gathered from 3767 autopsy cases and subdivided into intoxications by one substance only (Group A, n=611), multi-substance intoxications (Group B, n=1355) and postmortem controls, in which incapacitation by drugs were excluded (Group C, n=1801). In particular, this study presents statistical information about the precision and conformity change with various sample sizes.Based on the present data >10 detections are usually needed, for the substances examined, to differentiate between intoxication cases and controls. Repeated samplings show that the median of small samples (N=≤5) has a high variation (normalized interquartile range 138–75%) and that a high number of detections (N=>20) in each group are needed to reduce the variation.

Time- and temperature-dependent postmortem concentration changes of the (synthetic) cannabinoids JWH-210, RCS-4, as well as \u22069-tetrahydrocannabinol following pulmonary administration to pigs

In forensic toxicology, interpretation of postmortem (PM) drug concentrations might be complicated due to the lack of data concerning drug stability or PM redistribution (PMR). Regarding synthetic cannabinoids (SC), only sparse data are available, which derived from single case reports without any knowledge of dose and time of consumption. Thus, a controlled pig toxicokinetic study allowing for examination of PMR of SC was performed. Twelve pigs received a pulmonary dose of 200 µg/kg BW each of 4-ethylnaphthalene-1-yl-(1-pentylindole-3-yl)methanone (JWH-210), 2-(4-methoxyphenyl)-1-(1-pentyl-indole-3-yl)methanone (RCS-4), and Δ9-tetrahydrocannabinol via an ultrasonic nebulizer. Eight hours after, the pigs were put to death with T61 and specimens of relevant tissues and body fluids were collected. Subsequently, the animals were stored at room temperature (n = 6) or 4 °C (n = 6) and further samples were collected after 24, 48, and 72 h each. Concentrations were determined following enzymatic cleavage and solid-phase extraction by liquid-chromatography tandem mass spectrometry applying the standard addition approach. High concentrations of the parent compounds were observed in lung, liver, kidney and bile fluid/duodenum content as well as brain. HO-RCS-4 was the most prevalent metabolite detected in PM specimens. In general, changes of PM concentrations were found in every tissue and body fluid depending on the PM interval as well as storage temperature.

A Mechanism-Based Forensic Investigation into the Postmortem Redistribution of Morphine.

The interpretation of postmortem drug levels is complicated by the change in drug blood levels during the postmortem period, a phenomenon known as postmortem drug redistribution. We investigated the postmortem redistribution (PMR) of morphine, morphine-3-glucuronide and normorphine in the rat. Morphine (10mg/kg) was intravenously injected into rats, followed by euthanasia 1h post-injection. The carcasses were placed in a supine position at room temperature, and tissues including heart blood, femoral blood, liver, lung and brain were collected at different time points: 0, 8, 16 or 24h postmortem. The samples were analyzed with a validated (following modified Scientific Working Group for Forensic Toxicology (SWGTOX) (20) guidelines) liquid chromatography-tandem mass spectrometry method. The use of a mechanism-based approach (involving the used set doses of drug with the study performed in controlled environment) to assess PMR using systematic and statistical analyses provides important information that has not previously been presented in PMR literature. While previous human studies focus on central to peripheral ratios as well as peripheral to tissue ratio, this work focused on the change in morphine and metabolite concentrations over the course of the postmortem interval in relation to each other in addition to the comparison to additional matrices at each postmortem interval. Postmortem redistribution was identified in several tissues across the postmortem interval; however, there was minimal statistical difference observed among each matrix at a given postmortem interval with the exception of normorphine and morphine-3-glucuronide. Combined, our study provides a valuable resource and reference information that can aide toxicologists, medical examiners or coroners when assessing postmortem drug concentrations of morphine and metabolites when they are making determinations of cause of death.

Summary statistics for drug concentrations in post-mortem femoral blood representing all causes of death.

Concentration distributions for 183 drugs and metabolites frequently found in post-mortem (PM) femoral venous blood were statistically characterized based on an extensive database of 122 234 autopsy cases investigated during an 18-year period in a centralized laboratory. The cases represented all causes of death, with fatal drug poisonings accounting for 8%. The proportion of males was 74% with a median age of 58years compared with 26% females with a median age of 64years. In 36% of these cases, blood alcohol concentration was higher than or equal to 0.2‰, the median being 1.6‰. The mean, median, and upper percentile (90th, 95th, 97.5th) drug concentrations were established, as the median PM concentrations give an idea of the "normal" PM concentration level, and the upper percentile concentrations indicate possible overdose levels. A correspondence was found between subsets of the present and the previously published PM drug concentrations from another laboratory that grouped cases according to the cause of death. Our results add to the knowledge for evidence-based interpretation of drug-related deaths.

The relationship between antemortem and postmortem morphine concentrations

Context of the Article: An important forensic problem is whether the presence of a drug such as morphine caused or contributed to a death or was merely incidental. The reliance that can be based on postmortem drug concentrations remains controversial. To investigate this further we obtained antemortem and postmortem samples of individuals admitted to hospital who were receiving morphine and who died in hospital.Methods: Eleven subjects were recruited. Samples were sent for analysis for free and total morphine concentrations.Results: The median difference (postmortem – antemortem) free morphine concentration was 25.5 (range 0 to +126) µg/L, p < .01; the mean difference between postmortem and antemortem total morphine concentration was 34.5 (range −225 to 342) µg/L (not significant).Discussion: Our study supports previous investigators who note that there is an inconstant and sometimes tenuous relationship between ante- and postmortem morphine concentrations.

Utilizing postmortem drug concentrations in mechanistic modeling and simulation of cardiac effects: a proof of concept study with methadone

Methadone-related poisoning has been found to be the leading and increasing cause of death among intoxication cases in several countries. Aside from respiratory depression, methadone is known to cause QT-prolongation, which may lead to sudden cardiac death. Concentrations in heart tissue should be more accurate for estimating cardiotoxic effects. The aim of this study was to investigate whether the effect of methadone on the QT-interval could be simulated and whether the concentrations in heart tissues allowed for better prediction of the Bazett corrected QT-interval (QTcB). A predictive performance study was conducted using the simulation platform Cardiac Safety Simulator to mimic five literature studies using their described study conditions. Both free and total plasma and heart concentrations were investigated using two different in silico models: the O’Hara-Rudy (ORD) model and the 10 Tusscher (TNNP) model. The results showed that the QTcB of methadone was best predicted either with total plasma using the TNNP model or with free plasma using the ORD model. The ORD model was highly sensitive to the total heart concentrations, resulting in overprediction of the QTcB. The TNNP model also overpredicted the QTcB, but to a lesser degree than the ORD model. Furthermore, due to a low baseline QTcB, the ORD model underpredicted the QTcB for both the free plasma and free heart concentrations. In conclusion, it is possible to simulate the cardiac effects of methadone, yet several elements influence the approach uncertainty including but not limited to biophysically details model of cardiac electrophysiology, exposure data, and input parameters.

Comparative Study of Postmortem Concentrations of Antidepressants in Several Different Matrices

Peripheral blood (PB) is considered to be the golden standard for measuring postmortem drug concentrations. In several cases, PB is however not available, but information regarding drug findings might still be crucial in order to determine the cause of death. Antidepressants are frequently detected in postmortem samples from forensic toxicology cases, but the literature investigating concentrations in other matrices than peripheral and heart blood is limited.We here describe a study for comparison of concentrations for a large number of different drugs in six different matrices. A total of 173 postmortem cases were included in the study material. The results from 44 cases with findings of antidepressants (amitriptyline/nortriptyline, citalopram, mianserin, mirtazapine, paroxetine, sertraline, trimipramine and venlafaxine) are presented in this article. Concentrations in peripheral and cardiac blood (CB), pericardial fluid (PF), two muscle samples and vitreous humour (VH) are compared. Ratios between concentrations in different matrices have also been compiled from available literature.All the investigated antidepressants were detected in all different matrices, and comparable concentration levels were found in the different matrices with a few exceptions. Concentrations in VH were generally lower than in the other matrices, and in a few cases with low concentrations in blood the antidepressants were not detected in VH. For most of the cases, ratios of 0.5-2 were found between concentration in PB and that in the other matrices. Some deviant concentrations where however found.This study shows that CB, PF, muscle and VH can provide important indications of the corresponding concentrations in PB when PB is not available.

The toxicological significance of post-mortem drug concentrations in bile

Context: Some authors have proposed that post-mortem drug concentrations in bile are useful in estimating concentrations in blood. Both The International Association of Forensic Toxicologists (TIAFT) and the US Federal Aviation Administration recommend that samples of bile should be obtained in some circumstances. Furthermore, standard toxicological texts compare blood and bile concentrations, implying that concentrations in bile are of forensic value.Aim: To review the evidence on simultaneous measurements of blood and bile drug concentrations reported in the medical literature.Methods: We made a systematic search of EMBASE 1980–2016 using the search terms (“bile/” OR “exp drug bile level/concentration/”) AND “drug blood level/concentration/”, PubMed 1975–2017 for (“bile[tw]” OR “biliary[tw]”) AND (“concentration[tw]” OR “concentrations[tw]” OR “level[tw]” OR “levels[tw]”) AND “post-mortem[tw]” and also MEDLINE 1990–2016 for information on drugs whose biliary concentrations were mentioned in standard textbooks. The search was limited to human studies without language restrictions. We also examined recent reviews, indexes of relevant journals and citations in Web of Science and Google Scholar. We calculated the bile:blood concentration ratio. The searches together yielded 1031 titles with abstracts. We scanned titles and abstracts for relevance and retrieved 230, of which 161 were considered further. We excluded 49 papers because: the paper reported only one case (30 references); the data referred only to a metabolite (1); the work was published before 1980 (3); the information concerned only samples taken during life (10); or the paper referred to a toxin or unusual recreational drug (5). The remaining 112 papers provided data for analysis, with at least two observations for each of 58 drugs.Bile:blood concentration ratios: Median bile:blood concentration ratios varied from 0.18 (range 0.058–0.32) for dextromoramide to 520 (range 0.62–43,000) for buprenorphine. Median bile concentrations exceeded blood concentrations by one order of magnitude for several drugs, including dihydrocodeine, quetiapine and sildenafil; and by two orders of magnitude of for buprenorphine, colchicine and 3,4-methylenedioxy-methamphetamine (MDMA), among others. The minimum and maximum values for the ratio differed by a factor of three or more in three-quarters of the cases where data were available and by a factor of 10 or more for over half of the analytes.Limitations: The data were difficult to find. Medline does not explicitly index the term “drug bile concentration”. It may well be that other reports exist, although they would not alter our major conclusion. Many of the papers that contributed data failed to specify the source of the blood samples or the post-mortem interval, so that no judgment was possible regarding post-mortem redistribution in whole blood or bile.Conclusions: For most drugs, there are wide ranges of bile:blood concentration ratios, which means that bile and blood concentrations are generally poorly correlated. Bile concentration measurements cannot readily be used to establish post-mortem blood concentrations; nor can they be extrapolated to ante-mortem concentrations. However, because drug concentrations in bile often exceed those in blood, bile may allow qualitative identification of drugs present, even when the blood concentration is below the limit of detection.

Site-, Technique-, and Time-Related Aspects of the Postmortem Redistribution of Diazepam, Methadone, Morphine, and their Metabolites: Interest of Popliteal Vein Blood Sampling.

Sampling site, technique, and time influence postmortem drug concentrations. In 57 cases, we studied drug concentration differences as follows: subclavian vein-dissection/clamping versus blind stick, femoral vein-dissection/clamping versus blind stick, right cardiac chamber, and popliteal vein-dissection and clamping only. Cases were distributed in group #1 (all cases with both techniques), group #2 (dissection/clamping), and group #3 (blind stick). Sampled drugs were diazepam, methadone, morphine, and their metabolites. To assess PMR, mean concentrations and ratios were calculated for each group. Time-dependent variations of blood concentrations and ratios were also assessed. Results indicate that site, method, and time may influence postmortem distribution interpretation in different ways. Popliteal blood seems less subject to PMR. In conclusion, our study is the first to evaluate concurrently three main aspects of PMR and confirms that the popliteal vein may represent a site that is more resistant to the changes seen as a result of PMR.