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- Bastami, Salumeh, et al.
(författare)
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Influence of genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Purpose: There is a significant interindividual variation in the response to tramadol (TRA), which can partly be explained by genetic variation. The main purpose of this study was to determine if there is a correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA (MR) and time after drug administration. We also studied the association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA.Methods: Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report drug related symptoms (DRS) during the experimental day.Results: We found a positive correlation between MR and the time after drug intake for both intermediate metabolizers (IMs) and extensive metabolizers (EMs). For the only poor metabolizer (PM) with detectable ODT levels the MR was almost constant. The AUC MR and Cmax MR were associated with CYP2D6 genotype, showing the highest mean values for EMs. Multiple regression analysis showed that 56% of the variation in AUC MR could be explained by CYP2D6 alone and 78% by investigated SNPs altogether. There was great interindividual variation in DRS, but no associations could be found between DRS and investigated polymorphisms.Conclusions: MR can be used for estimation of the time of drug intake when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study. We propose that pharmacogenetics should be taken into consideration when interpreting clinical pharmacology and forensic toxicology results, more specifically CYP2D6 genotypes when interpreting the pharmacokinetics of TRA.
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| 2. |
- Bastami, Salumeh, et al.
(författare)
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Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
- 2014
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Ingår i: Forensic Science International. - : Elsevier. - 0379-0738 .- 1872-6283. ; 238, s. 125-132
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Tidskriftsartikel (refereegranskat)abstract
- The major purpose of this study was to elucidate if genotyping can facilitate interpretations of tramadol (TRA) in forensic case work, with special regard to the estimation of the time of drug intake and drug related symptoms (DRS). The association between genetic polymorphisms in CYP2D6, OPRM1 and ABCB1 and pharmacokinetic and pharmacodynamic properties of TRA was studied. Nineteen healthy volunteers were randomized into two groups receiving a single dose of either 50 or 100 mg of orally administrated TRA. Blood samples were collected prior to dosing and up to 72 h after drug intake. The subjects were asked to report DRS during the experimental day. We found a positive correlation between the metabolic ratio of O-desmethyltramadol (ODT) to TRA and the time after drug intake for both CYP2D6 intermediate metabolizers and extensive metabolizers. For the only poor metabolizer with detectable ODT levels the metabolic ratio was almost constant. Significant associations were found between the area under the concentration-time curve (AUC) and three of the investigated ABCB1 single nucleotide polymorphisms for TRA, but not for ODT and only in the 50 mg dosage group. There was great interindividual variation in DRS, some subjects exhibited no symptoms at all whereas one subject both fainted and vomited after a single therapeutic dose. However, no associations could be found between DRS and investigated polymorphisms. We conclude that the metabolic ratio of ODT/TRA may be used for estimation of the time of drug intake, but only when the CYP2D6 genotype is known and taken into consideration. The influence of genetic polymorphisms in ABCB1 and OPRM1 requires further study.
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| 3. |
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| 4. |
- Boiso, Samuel, et al.
(författare)
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ABCB1 gene polymorphisms are associated with suicide in forensic autopsies
- 2013
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Ingår i: Pharmacogenetics & Genomics. - : Lippincott, Williams and Wilkins. - 1744-6872 .- 1744-6880. ; 23:9, s. 463-469
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Tidskriftsartikel (refereegranskat)abstract
- Background Polymorphisms in ABCB1 have the ability to affect both the function and the expression of the transporter protein P-glycoprotein and may lead to an altered response for many drugs including some antidepressants and antipsychotics.Objective The aim of this study was to examine the impact of the ABCB1 polymorphisms 1199Gandgt;A, 1236Candgt;T, 2677Gandgt;T/A, and 3435Candgt;T in deaths by suicide.Patients and methods A total of 998 consecutive Swedish forensic autopsies performed in 2008 in individuals 18 years of age or older, where femoral blood was available and a toxicological screening had been performed, were investigated. Genotypes were assessed with pyrosequencing and information on the cause and manner of each death was obtained from the forensic pathology and toxicology databases.Results There was a significantly higher frequency of the T allele at positions 1236, 2677, and 3435 among the suicide cases compared with the nonsuicide cases.Conclusion Our result from forensic cases suggests that ABCB1 polymorphisms are associated with an increased risk for completed suicides. The biological mechanisms involved and the clinical implications for these findings are largely unknown and need to be examined further.
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| 8. |
- Druid, Henrik, et al.
(författare)
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Evaluation of the role of abstinence in heroin overdose deaths using segmental hair analysis
- 2007
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Ingår i: Forensic Science International. - : Elsevier BV. - 0379-0738 .- 1872-6283. ; 168:2-3, s. 223-226
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Tidskriftsartikel (refereegranskat)abstract
- In the body heroin is rapidly metabolized to 6-acetylmorphine and morphine. Victims of lethal heroin overdose often present with fairly low blood concentrations of morphine. Reduced tolerance due to abstinence has been proposed to account for this finding. The aim of the present study was to examine the role of abstinence in drug-related deaths by comparing recent and past exposure to opioids using segmental hair analysis with the postmortem blood morphine concentrations in deceased heroin users. The study included 60 deceased drug addicts in the Stockholm area, Sweden. In 32 cases, death was not related to heroin intake. In 18 of the 28 heroin fatalities, opioids were absent in the most recent hair segment, suggesting a reduced tolerance to opioids. However, the blood morphine levels were similar to those found in the 10 subjects that showed continuous opioid use. Hair and blood analysis disclosed an extensive use of additional drugs that directly or indirectly may influence the opioid system. The results suggest that abstinence is not a critical factor for heroin overdose death. Obviously tolerant subjects die after intake of similar doses. Other factors, particularly polydrug use, seem to be more causally important for these deaths.
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| 9. |
- Elmsjo, Albert, et al.
(författare)
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Post-Mortem Metabolomics: A Novel Approach in Clinical Biomarker Discovery and a Potential Tool in Death Investigations
- 2021
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Ingår i: Chemical Research in Toxicology. - : AMER CHEMICAL SOC. - 0893-228X .- 1520-5010. ; 34:6, s. 1496-1502
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Tidskriftsartikel (refereegranskat)abstract
- Metabolomics can be defined as the scientific field aiming at characterizing all low-weight molecules (so-called metabolites) in a biological system. At the time of death, the level and type of metabolites present will most likely reflect the events leading up to death. In this proof of concept study, we investigated the potential of post-mortem metabolomics by identifying post-mortem biomarkers, correlated these identified biomarkers with those reported in clinical metabolomics studies, and finally validated the models predictability of unknown autopsy cases. In this post-mortem metabolomics setting, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry data from 404 post-mortem samples, including pneumonia cases and control cases, were processed using XCMS (R). Potential biomarkers were evaluated using principal component analysis and orthogonal partial least squares-discriminant analysis. Biomarkers were putatively annotated using an in-house database and the online databases METLIN and HMDB. The results showed that clear group separation was observed between pneumonia cases and control cases. The metabolites responsible for group separation belonged to a broad set of biological classes, such as amino acids, carnitines, lipids, nicotinamides, nucleotides, and steroids. Many of these metabolites have been reported as important in clinical manifestation of pneumonia. For the unknown autopsy cases, the sensitivity and specificity were 86 and 84%, respectively. This study successfully investigated the robustness and usability of post-mortem metabolomics in death investigations. The identified post-mortem biomarkers correlated well with biomarkers reported and identified through clinical research.
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