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Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linköping, Sweden.
Vise andre og tillknytning
2014 (engelsk)Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 238, s. 125-132Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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.

sted, utgiver, år, opplag, sider
Elsevier, 2014. Vol. 238, s. 125-132
Emneord [en]
Tramadol; Pharmacokinetics; Pharmacodynamics; CYP2D6; ABCB1; OPRM1
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-106838DOI: 10.1016/j.forsciint.2014.03.003ISI: 000334580700025PubMedID: 24709712OAI: oai:DiVA.org:liu-106838DiVA, id: diva2:720137
Tilgjengelig fra: 2014-05-28 Laget: 2014-05-23 Sist oppdatert: 2018-11-09bibliografisk kontrollert
Inngår i avhandling
1. Forensic Toxicological Aspects of Tramadol: Focus on Enantioselective Drug Disposition and Pharmacogenetics
Åpne denne publikasjonen i ny fane eller vindu >>Forensic Toxicological Aspects of Tramadol: Focus on Enantioselective Drug Disposition and Pharmacogenetics
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

One of the most difficult parts in forensic toxicology is to interpret obtained drug concentrations. Was it therapeutic, toxic or even lethal to the particular individual that the blood sample was drawn from? Concentrations of opioid drugs are especially difficult to interpret, because of large interindividual differences in innate and acquired tolerance.

Tramadol is a complex drug. Not only is it an opioid, it is also a racemic drug with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. Further, it is metabolized by polymorphic enzymes, which may affect the amounts of metabolites formed and possibly the enantiomer ratios of the parent compound and its metabolites. It has been speculated that particularly the (+)/(-)-enantiomer ratio of O-desmethyltramadol is related to the risk of adverse effects, and it has been shown that the ratio is affected by CYP2D6 genotype.

The overall aim of the thesis was to evaluate if forensic interpretations of tramadol, regarding toxicity and time since drug administration, may be improved by the use of genotyping and enantioselective concentration determination of tramadol and its three main metabolites.

To simultaneously quantify the enantiomer concentrations of tramadol, Odesmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol in whole blood, a liquid chromatography tandem mass spectrometry (LCMS/MS) method was developed and validated. Genetic variation in CYP2D6, CYP2B6, CYP3A4 (encoding the tramadol metabolizing enzymes), ABCB1 (encoding a transport protein) and OPRM1 (encoding the μ-opioid receptor) was investigated, using pyrosequencing, xTAG, and TaqMan analysis. The methods were applied to the blood samples of two study populations; 19 healthy volunteers administered a therapeutic, single tramadol dose, and 159 tramadol positive autopsy cases.

The most important finding was the positive correlations between all four enantiomer ratios and time since tramadol administration in the healthy volunteers. All enantiomer ratios except the one of tramadol was also affected by the CYP2D6 genotype, which was apparent among the autopsy cases as well. Genetic variation in CYP2D6 and possibly CYP2B6 was shown to have an impact on tramadol pharmacokinetics, although no association to neither drug related symptoms nor tramadol related causes of death was found. Tramadol intoxications were predominantly characterized by low age (median 26 years) and male sex, often with a history of substance abuse and with other drugs (at fairly low concentrations) detected in blood.

In conclusion, enantiomer concentration determination combined with genotyping seems promising regarding estimations of time since drug administration, although is of low value concerning interpretations of toxicity in autopsy cases.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2018. s. 104
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1647
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-152626 (URN)10.3384/diss.diva-152626 (DOI)9789176851968 (ISBN)
Disputas
2018-11-30, Berzeliussalen, Campus US, Linköping, 13:00 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-11-09 Laget: 2018-11-09 Sist oppdatert: 2019-09-30bibliografisk kontrollert

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