A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine

Jornil, Jakob; Nielsen, Trine Skov; Rosendal, Ingrid; Ahlner, Johan; Zackrisson, Anna Lena; Boel, Lene Warner Thorup; Brock, Birgitte

doi:10.1016/j.forsciint.2012.12.020

Cited by 35 publications

(35 citation statements)

References 44 publications

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“…As a consequence, there may be symptoms of overdose where the dosage is not matched with individual metabolic capacity, or where there are toxic metabolites. This has been documented in vitro and in vivo for psychiatric drugs (e.g., quetiapine, venlafaxine and trazodone) (Jornil et al, 2013;Li & Cameron, 2012;Najibi et al, 2016). Other examples include primaquine (Ganesan,…”

Section: Cyp2d6mentioning

confidence: 95%

Prediction of clinically relevant drug‐induced liver injury from structure using machine learning

Hammann

Schöning

Drewe

2018

J of Applied Toxicology

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Drug‐induced liver injury (DILI) is the most common cause of acute liver failure and often responsible for drug withdrawals from the market. Clinical manifestations vary, and toxicity may or may not appear dose‐dependent. We present several machine‐learning models (decision tree induction, k‐nearest neighbor, support vector machines, artificial neural networks) for the prediction of clinically relevant DILI based solely on drug structure, with data taken from published DILI cases. Our models achieved corrected classification rates of up to 89%. We also studied the association of a drug's interaction with carriers, enzymes and transporters, and the relationship of defined daily doses with hepatotoxicity. The results presented here are useful as a screening tool both in a clinical setting in the assessment of DILI as well as in the early stages of drug development to rule out potentially hepatotoxic candidates.

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Section: Cyp2d6mentioning

confidence: 95%

Prediction of clinically relevant drug‐induced liver injury from structure using machine learning

Hammann

Schöning

Drewe

2018

J of Applied Toxicology

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“…Determination of status of cytochrome P450 and enzyme CYP2D6, which play a central role in the metabolism of drugs in the human body, can reveal poor metabolizer, causing reduced metabolic capacity and fatal drug poisoning. This method, combined with genotyping, can detect fatal drug poisoning involving psychoactive agents, as it was reported with venlafaxine, oxycodone, and ethanol for example or with doxepin alone . Genetic changes in the CYP2D6 gene can lead to reduced or absent activity .…”

Section: Discussionmentioning

confidence: 99%

Undetermined Manner of Death: An Autopsy Series

Advenier

Guillard

Alvarez

et al. 2015

Journal of Forensic Sciences

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A manner of death may be ruled undetermined by the forensic pathologist when there is insufficient information about the circumstances surrounding the death to make a ruling. The aim of our study was to retrospectively analyze a series of autopsy cases that were classified as undetermined manner of death after complete investigations. In all, 48 cases were examined. In 23 cases (48%), the cause of death was determined. The most frequent cause of death was toxic death (n = 11). More than one manner of death was deemed conceivable for most cases (n = 39). The most frequent and the most probable manner of death was accident (n = 37). Homicide was not excluded in about 23% of the cases. Our study showed that the manner of death may remain undetermined despite an established cause of death, and even when two or more conceivable causes of death are considered. Our study pointed out that undetermined manner of death covers a wide range of situations and that homicide may be underestimated.

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“…The evidence for the effects of CYP2D6 polymorphism on the PK of CNSactive CYP2D6 substrates is clearly given [14][15][16][17][18][19][20][21][24][25][26][27][28][29][30][31][32], and CYP2D6 genotyping can definitely help avoid serious adverse reactions. However, the ultimate proof for a clear link to the clinical outcome/endpoints is still lacking.…”

Section: Discussionmentioning

confidence: 99%

“…The risk is not limited to the direct use in children after tonsillectomy but also applies to breastfeeding mothers treated with codeine [15][16][17][18][19][20][21]. Other examples are tardive dyskinesia after metoclopramide in PMs [22,23]; cardiac and neurotoxic effects with tricyclic antidepressants in PMs [24][25][26], but also with some newer antidepressants such mirtazapine [27,28] in UMs and venlafaxine in PMs [29,30]; and the higher incidence of Parkinson-like symptoms in PMs treated with typical antipsychotics such as haloperidol [31]. While in the beginning, mostly CNS and cardiovascular drugs were in the focus [32], the efficacy of the antiestrogen tamoxifen has been shown to be linked to the CYP2D6 genotype [33].…”

Section: Introductionmentioning

confidence: 99%

Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

Haertter

2013

Drug Metabolism and Drug Interactions

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The cytochrome P450 2D6 (CYP2D6) belongs to a group of CYPs considered of utmost importance in the metabolism of xenobiotics. Despite being of only minor abundance in the liver, it is involved in the clearance of >25% of marketed drugs. Accordingly, CYP2D6 can be very efficiently inhibited by a couple of commonly used drugs such as some antidepressants, although induction by any drug has not been observed thus far. CYP2D6 was also one of the first enzymes for which a highly polymorphic expression could be shown leading to a widespread range of functionality, from a complete lack of a functional enzyme to overexpression due to multiplication of active alleles. A clear relationship between the CYP2D6 genotype and adverse events during treatment with CNS-active drugs such as codeine, antidepressants, or antipsychotics could be demonstrated. More recently, some new aspects emerged about the potential endogenous function of CYP2D6 in terms of behavior and brain disorders.

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A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine

Cited by 35 publications

References 44 publications

Prediction of clinically relevant drug‐induced liver injury from structure using machine learning

Prediction of clinically relevant drug‐induced liver injury from structure using machine learning

Undetermined Manner of Death: An Autopsy Series

Recent examples on the clinical relevance of the CYP2D6 polymorphism and endogenous functionality of CYP2D6

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