Pharmacogenomics as Molecular Autopsy for Forensic Toxicology: Genotyping Cytochrome P450 3A4*1B and 3A5*3 for 25 Fentanyl Cases

Jin, Ming; Gock, Susan B.; Jannetto, Paul J.; Jentzen, Jeffrey M.; Wong, Steven H.

doi:10.1093/jat/29.7.590

Cited by 87 publications

(34 citation statements)

References 10 publications

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“…In the living, the dose administered generally correlates with measured blood concentrations. In the postmortem setting, however, there are several factors that may affect the concentration and should be considered when interpreting postmortem concentrations [7,[25][26][27][28][29]. These include tolerance, postmortem intervals and redistribution, and metabolism.…”

Section: Discussionmentioning

confidence: 99%

Reliability of Postmortem Fentanyl Concentrations in Determining the Cause of Death

2012

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Introduction Transdermal fentanyl, an opioid used for management of marked pain, also is abused and may cause death. Methods We reviewed medical examiner reports of 92 decedents who had one or more fentanyl transdermal patches on their body and had fentanyl detected in their postmortem toxicology analysis. Results The manners of death included 40 accidents, 36 natural, 8 suicides, 5 therapeutic complications, and 3 undetermined deaths. Among the accidental fentanyl intoxication deaths, 32 of 37 involved substance abuse. The majority (95 %) of the 37 accidental deaths involving fentanyl were multi-drug intoxications. The substance abuse deaths had a mean fentanyl blood concentration (26.4 ng/ml or μg/L) that was over twice that of the natural group (11.8 ng/ml). Our analysis suggests a relationship between total patch dosage and mean postmortem fentanyl concentration up to the 100-μg/h dose. Conclusions The very wide and overlapping ranges of postmortem fentanyl concentrations effectively nullify the utility of correlating the dose and expected postmortem concentration for any particular death. Based on the variable relationship between dose and blood concentration, the antemortem dose cannot be reliably predicted based on the postmortem concentration. This does not, however, render the medical examiner/coroner unable to determine the cause and manner of death because the toxicology results are only one datum point among several that are considered. Although there was a weakly positive relationship between body mass index and fentanyl concentration, further research is needed to determine whether adipose tissue represents a significant depot for postmortem release of fentanyl.Keywords Toxicology . Fentanyl . Fatality . Forensic pathology . Transdermal . Intoxication Fentanyl, a synthetic phenylpiperidine, is a prescription opioid that is used for management of marked pain and the induction of anesthesia [1][2][3]. It has agonist activity at the μ-opioid receptor that results in analgesia and euphoria and is a schedule II medication that has a high potential for abuse. It may be administered by intravenous, transdermal, epidural, transmucosal, and inhalational routes. Due to slow absorption, the transdermal route is prescribed only for treatment of chronic pain. Transdermal (TD) delivery occurs by passive diffusion of fentanyl through the epidermis and dermis into the systemic circulation. Due to fentanyl's lipophilicity, it rapidly diffuses through the epidermis but is delayed by the water-rich dermis. This results in a depot of fentanyl at the epidermis-dermal junction, which explains both the slow onset and prolonged effects of TD fentanyl that may continue even after removal of an unspent patch.We have reviewed 92 deaths in which the decedent was found to be using one or more fentanyl patches. The causes of death, indication for use, evidence of abuse, postmortem toxicologic results with concentrations, and the epidemiology are examined and discussed. Our goal is to examine the relationship between the...

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Section: Discussionmentioning

confidence: 99%

Reliability of Postmortem Fentanyl Concentrations in Determining the Cause of Death

2012

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“…Nonetheless, a significant number of anatomically apparent causes of sudden death also have a heritable component; these and other subtle potential causes of sudden death should be excluded before resorting to a diagnosis of likely channelopathy. However, it is becoming apparent that genetic heterogeneity may account for individual susceptibilities [542][543][544]; thus it may be that genetics, including channelopathies, will be shown to play a role in explaining why sudden death occurs in some victims of chronic disease and not in others.…”

Section: Resultsmentioning

confidence: 99%

Sudden adult death

Langlois

2009

Forensic Sci Med Pathol

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In the investigation of sudden death in adults, channelopathies, such as long QT syndrome, have risen to the fore in the minds of forensic pathologists in recent years. Examples of these disorders are touched upon in this review as an absence of abnormal findings at postmortem examination is characteristic and the importance of considering the diagnosis lies in the heritable nature of these conditions. Typically, a diagnosis of a possible channelopathy is evoked as an explanation for a 'negative autopsy' in a case of apparent sudden natural death. However, the one potential adverse effect of this approach is that subtle causes of sudden death may be overlooked. The intention of this article is to review and discuss potential causes of sudden adult death (mostly natural) that should be considered before resorting to a diagnosis of possible channelopathy. Nonetheless, it becomes apparent that many of the potential causes of sudden death can have a genetic basis. Thus, it becomes an important consideration that there may be a genetic basis to sudden death that extends beyond the negative autopsy.

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“…Postmortem and in vivo studies have provided the fi rst scientifi c evidence that CYP3A5 is involved in fentanyl metabolism, and homozygous CYP3A5*3 causes impaired metabolism of fentanyl. The authors have suggested that genotyping for CYP3A4*1B and 3A5*3 variants may help to confi rm fentanyl toxicity (209).…”

Section: Cyp3a4/5mentioning

confidence: 99%

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Božina¹,

Bradamante

Lovrić

2009

Archives of Industrial Hygiene and Toxicology

165

111

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The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.

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Pharmacogenomics as Molecular Autopsy for Forensic Toxicology: Genotyping Cytochrome P450 3A41B and 3A53 for 25 Fentanyl Cases

Cited by 87 publications

References 10 publications

Reliability of Postmortem Fentanyl Concentrations in Determining the Cause of Death

Reliability of Postmortem Fentanyl Concentrations in Determining the Cause of Death

Sudden adult death

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

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