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Zackrisson, Anna-Lena
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Publications (10 of 20) Show all publications
Karlsson, L., Zackrisson, A. L., Josefsson, M., Carlsson, B., Green, H. & Kugelberg, F. . (2015). Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.. The Pharmacogenomics Journal, 15(2), 165-71
Open this publication in new window or tab >>Influence of CYP2D6 and CYP2C19 genotypes on venlafaxine metabolic ratios and stereoselective metabolism in forensic autopsy cases.
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2015 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 15, no 2, p. 165-71Article in journal (Refereed) Published
Abstract [en]

We investigated whether polymorphisms in the CYP2D6 and CYP2C19 genes influence the metabolic ratios and enantiomeric S/R ratios of venlafaxine (VEN) and its metabolites O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV) and N,O-didesmethylvenlafaxine (DDV) in blood from forensic autopsy cases. In all, 94 postmortem cases found positive for VEN during toxicological screening were included. The CYP2D6 genotype was shown to significantly influence the ODV/VEN (P=0.003), DDV/NDV (P=0.010) and DDV/ODV (P=0.034) ratios. The DDV/ODV (P=0.013) and DDV/VEN (P=0.021) ratios were significantly influenced by the CYP2C19 genotype. The S/R ratios of VEN were significantly influenced by both CYP2D6 and CYP2C19 genotypes. CYP2D6 poor metabolizers (PMs) had lower S/R VEN ratios and CYP2C19 PMs had high S/R ratios of VEN in comparison. Our results show that the CYP2D6 genotype influences the O-demethylation whereas CYP2C19 influences the N-demethylation of VEN and its metabolites. In addition, we show a stereoselective metabolism where CYP2D6 favours the R-enantiomer whereas CYP2C19 favours the S-enantiomer.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-116540 (URN)10.1038/tpj.2014.50 (DOI)000351780200008 ()25245581 (PubMedID)
Available from: 2015-03-27 Created: 2015-03-27 Last updated: 2018-01-11
Bastami, S., Gupta, A., Zackrisson, A. L., Ahlner, J., Osman, A. & Uppugunduri, S. (2014). Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on morphine use. Basic & Clinical Pharmacology & Toxicology, 115(5), 423-431
Open this publication in new window or tab >>Influence of UGT2B7, OPRM1 and ABCB1 gene polymorphisms on morphine use
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2014 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 115, no 5, p. 423-431Article in journal (Refereed) Published
Abstract [en]

Therapeutic modulation of pain with morphine and other opioids is associated with significant variation in, both, effects and adverse effects in individual patients. Many factors including gene polymorphisms have been shown to contribute to the interindividual variability in the response to opioids. The aim of this study was to investigate the significance of UGT2B7, OPRM1 and ABCB1 polymorphisms for interindividual variability in morphine induced analgesia in patients undergoing hysterectomy. The frequency of these polymorphisms was also investigated in forensic autopsy cases as morphine is also a very commonly abused drug

Blood samples were collected from 40 patients following abdominal hysterectomy, 24 hours after initiation of analgesia through a PCA pump. Samples were genotyped and analysed for morphine and its metabolites. We also genotyped approximately 200 autopsy cases found positive for morphine in routine forensic analysis.

Patients homozygous for UGT2B7 802C needed significantly lower dose of morphine for pain relief. The same trend was observed for patients homozygous for ABCB1 1236T and 3435T, as well as to OPRM1 118A. Dose of morphine in patients included in this study was significantly related to variation in UGT2B7 T802C. Age was significantly related to both dose and concentration of morphine in blood.

Regression analysis showed that 30% of differences in variation in morphine dose could be explained by SNPs in these genes. The genotype distribution was similar between the forensic cases and the patients. However, the mean concentration of morphine was higher in forensic cases compared to patients.

We conclude that gene polymorphisms contribute significantly to the variation in morphine levels observed in individual patients.

Place, publisher, year, edition, pages
Wiley, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-96791 (URN)10.1111/bcpt.12248 (DOI)000344015300008 ()24703092 (PubMedID)
Available from: 2013-08-27 Created: 2013-08-27 Last updated: 2017-12-06Bibliographically approved
Bastami, S., Haage, P., Kronstrand, R., Kugelberg, F., Zackrisson, A.-L. & Uppugunduri, S. (2014). Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose. Forensic Science International, 238, 125-132
Open this publication in new window or tab >>Pharmacogenetic aspects of tramadol pharmacokinetics and pharmacodynamics after a single oral dose
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2014 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 238, p. 125-132Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Tramadol; Pharmacokinetics; Pharmacodynamics; CYP2D6; ABCB1; OPRM1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-106838 (URN)10.1016/j.forsciint.2014.03.003 (DOI)000334580700025 ()24709712 (PubMedID)
Available from: 2014-05-28 Created: 2014-05-23 Last updated: 2018-11-09Bibliographically approved
Jornil, J., Nielsen, T. S., Rosendal, I., Ahlner, J., Zackrisson, A. L., Boel, L. W. & Brock, B. (2013). A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine. Forensic Science International, 226(1-3), E26-E31
Open this publication in new window or tab >>A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine
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2013 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 226, no 1-3, p. E26-E31Article in journal (Refereed) Published
Abstract [en]

We present a fatal drug poisoning case involving venlafaxine (VEN). The deceased took his medication regularly (including 150 mg VEN twice daily), and nothing in the case or autopsy findings pointed towards suicide. The toxicological assessment concluded that the cause of death was most likely due to a poisoning with a combination of VEN, oxycodone and ethanol, and the manner of death was considered to be an accident. The blood concentration of VEN was high (4.5 mg/kg), and the ratio of the VEN metabolite O-desmethylvenlafaxine (ODV) to VEN was exceptionally low (0.006). Mechanistic pharmacokinetic simulations suggested that the low metabolite ratio was the result of combined poor metabolizer (PM) status of cytochrome P450 (CYP) 2C19 and CYP2D6. This hypothesis was confirmed by genetic analysis. Simulations revealed that it was likely that the combined missing CYP2D6 and CYP2C19 activity would cause higher concentrations of VEN, but the simulations also suggested that there could be additional reasons to explain the high VEN concentration found in this case. Thus, it seems likely that the potentially toxic VEN concentration was caused by reduced metabolic capacity. The simulations combined with genotyping were considered very useful in this fatal drug poisoning case.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
CYP2D6, CYP2C19, Venlafaxine, Poor metabolizer, Drug poisoning, Mechanistic pharmacokinetic simulation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-91940 (URN)10.1016/j.forsciint.2012.12.020 (DOI)000316792100007 ()
Available from: 2013-05-06 Created: 2013-05-06 Last updated: 2017-12-06
Karlsson, L., Green, H., Zackrisson, A. L., Bengtsson, F., Jakobsen Falk, I., Carlsson, B., . . . Kugelberg, F. (2013). ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram. International journal of legal medicine (Print), 127(3), 579-586
Open this publication in new window or tab >>ABCB1 gene polymorphisms are associated with fatal intoxications involving venlafaxine but not citalopram
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2013 (English)In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 127, no 3, p. 579-586Article in journal (Refereed) Published
Abstract [en]

P-glycoprotein (P-gp), encoded by the ABCB1/MDR1 gene, is a drug transporter at the blood–brain barrier. Several polymorphisms in the ABCB1 gene are known to affect the activity and/or expression of P-gp, thereby influencing the treatment response and toxicity of P-gp substrates like citalopram and venlafaxine. In this study, we aimed to investigate the frequency of ABCB1 genotypes in forensic autopsy cases involving these two antidepressants. Further, the distribution of ABCB1 genotypes in deaths related to intoxication was compared to cases not associated to drug intoxication. The study included 228 forensic autopsy cases with different causes and manners of deaths. The ABCB1 single nucleotide polymorphisms (SNPs) G1199A, C1236T, C3435T and G2677T/A for these individuals were determined. The SNPs C1236T and C3435T in venlafaxine-positive cases were significantly different between the intoxication cases and non-intoxications. This was not seen for cases involving citalopram, indicating that the effect of genetic variants might be substrate specific. This novel finding should, however, be confirmed in future studies with larger number of cases.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2013
Keywords
ABCB1, Citalopram, Forensic material, Genotype, Postmortem, Venlafaxine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-93390 (URN)10.1007/s00414-013-0849-0 (DOI)000318247100006 ()
Note

Funding Agencies|National Board of Forensic Medicine in Sweden||Swedish Research Council||

Available from: 2013-05-31 Created: 2013-05-31 Last updated: 2017-12-06Bibliographically approved
Boiso, S., Zackrisson, A. L., Jakobsen Falk, I., Karlsson, L., Carlsson, B., Tillmar, A., . . . Green, H. (2013). ABCB1 gene polymorphisms are associated with suicide in forensic autopsies. Pharmacogenetics & Genomics, 23(9), 463-469
Open this publication in new window or tab >>ABCB1 gene polymorphisms are associated with suicide in forensic autopsies
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2013 (English)In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 23, no 9, p. 463-469Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Lippincott, Williams and Wilkins, 2013
Keywords
ABCB1, autopsy, forensic material, genotype, postmortem, sex, suicide
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97235 (URN)10.1097/FPC.0b013e328363a9bf (DOI)000323220200002 ()
Note

Funding Agencies|National Board of Forensic Medicine in Sweden||Swedish Research Council||Swedish Cancer Society||

Available from: 2013-09-06 Created: 2013-09-05 Last updated: 2017-12-06
Kingbäck, M., Karlsson, L., Zackrisson, A.-L., Josefsson, M., Carlsson, B., Bengtsson, F., . . . Kugelberg, F. C. (2012). Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood. Forensic Science International, 214(1-3), 124-134
Open this publication in new window or tab >>Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood
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2012 (English)In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 214, no 1-3, p. 124-134Article in journal (Refereed) Published
Abstract [en]

Venlafaxine (VEN) is an antidepressant drug mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to the active metabolite O-desmethylvenlafaxine (ODV). VEN is also metabolized to N-desmetylvenlafaxine (NDV) via CYP3A4. ODV and NDV are further metabolized to N,O-didesmethylvenlafaxine (DDV). VEN is a racemic mixture of the S- and R-enantiomers and these have in vitro displayed different degrees of serotonin and noradrenaline reuptake inhibition. The aim of the study was to investigate if an enantioselective analysis of VEN and its metabolites, in combination with genotyping for CYP2D6, could assist in the interpretation of forensic toxicological results in cases with different causes of deaths. Concentrations of the enantiomers of VEN and metabolites were determined in femoral blood obtained from 56 autopsy cases with different causes of death. The drug analysis was done by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the CYP2D6 genotyping by PCR and pyrosequencing. The mean (median) enantiomeric S/R ratios of VEN, ODV, NDV and DDV were 0.99 (0.91), 2.17 (0.93), 0.92 (0.86) and 1.08 (1.03), respectively. However, a substantial variation in the relationship between the S- and R-enantiomers of VEN and metabolites was evident (S/R ratios ranging from 0.23 to 17.6). In six cases, a low S/R VEN ratio (mean 0.5) was associated with a high S/R ODV ratio (mean 11.9). Genotyping showed that these individuals carried two inactive CYP2D6 genes indicating a poor metabolizer phenotype. From these data we conclude that enantioselective analysis of VEN and ODV can predict if a person is a poor metabolizer genotype/phenotype for CYP2D6. Knowledge of the relationship between the S- and R-enantiomers of this antidepressant drug and its active metabolite is also important since the enantiomers display different pharmacodynamic profiles.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
CYP2D6; Enantiomers; Forensic toxicology; Postmortem toxicology; Venlafaxine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72238 (URN)10.1016/j.forsciint.2011.07.034 (DOI)000298634900032 ()21840145 (PubMedID)
Note

Funding agencies|Forensic Science Center of Linkoping University||National Board of Forensic Medicine in Sweden||Swedish Research Council| 2009-4740 |

Available from: 2011-11-23 Created: 2011-11-23 Last updated: 2017-12-08Bibliographically approved
Ahlner, J., Zackrisson, A. L., Lindblom, B. & Bertilsson, L. (2010). Editorial Material: CYP2D6, serotonin and suicide. Pharmacogenomics (London), 11(7), 903-905
Open this publication in new window or tab >>Editorial Material: CYP2D6, serotonin and suicide
2010 (English)In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 11, no 7, p. 903-905Article in journal, Editorial material (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Future Medicine, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-58184 (URN)10.2217/PGS.10.84 (DOI)000280007600001 ()
Available from: 2010-08-11 Created: 2010-08-09 Last updated: 2017-12-12
Zackrisson, A.-L., Lindblom, B. & Ahlner, J. (2009). High Frequency of Occurrence of CYP2D6 Gene Duplication/Multiduplication Indicating Ultrarapid Metabolism Among Suicide Cases: High frequency of CYP2D6 ultra-rapid metabolizers among suicide cases. Clinical Pharmacology and Therapeutics
Open this publication in new window or tab >>High Frequency of Occurrence of CYP2D6 Gene Duplication/Multiduplication Indicating Ultrarapid Metabolism Among Suicide Cases: High frequency of CYP2D6 ultra-rapid metabolizers among suicide cases
2009 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535Article in journal (Other academic) Published
Abstract [en]

In Sweden about 550 individuals die every year due to intoxication with drugs. Many of these drugs are metabolized by CYP-enzymes, such as CYP2D6 and CYP2C19. Lack of these enzymes, resulting in a poor metabolism, can lead to adverse reactions, even leading to a fatal outcome. On the other hand, socalled ultra-rapid metabolism can lead to insufficient drug plasma concentration and with that failed treatment or it can lead to a high amount of active/toxic metabolites. The aim of this project was to study the genetic distributions of CYP2D6 and CYP2C19 in fatal intoxication cases (242), suicide cases (intoxications excluded) (262) and natural death cases (212). PCR followed by pyrosequencing was used for all the analyses. Surprisingly, we found an increased number of individuals carrying more than two active CYP2D6 alleles, corresponding to the phenotype of an ultra-rapid metabolizer, among the suicide cases as compared to the natural death cases (p=0.007).

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17935 (URN)10.1038/clpt.2009.216 (DOI)
Available from: 2009-04-27 Created: 2009-04-27 Last updated: 2017-12-13Bibliographically approved
Zackrisson, A.-L. (2009). Pharmacogenetics from a Forensic Perspective: CYP2D6 and CYP2C19 genotype distributions in autopsy cases. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Pharmacogenetics from a Forensic Perspective: CYP2D6 and CYP2C19 genotype distributions in autopsy cases
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In Sweden about 550 individuals die every year due to drug intoxication. A challenge for the forensic toxicologist is to determine whether or not the analytical results can explain intoxication as a cause of death. The most common drugs found among intoxication cases are psychiatric drugs and analgesics. Many of these drugs are metabolised by CYP-enzymes such as CYP2D6 and CYP2C19. Genetic variations, polymorphisms, in the genes coding for these enzymes can lead to an inactive enzyme resulting in poor metabolism, which can lead to adverse drug reactions, even with fatal outcome. The CYP2D6 gene can be multiplied, which can lead to an ultra-rapid metabolism if the alleles are active. Another polymorphism, in the CYP2C19 gene, can also lead to an ultra-rapid metabolism. This increased metabolism can result in insufficient drug plasma concentration and, with that, failed treatment. Alternately, if the drug is a pro-drug and has to be activated by these enzymes, it can lead to a high amount of active metabolites. There is a large inter-individual variation of these polymorphisms and also a large variation between different populations. Additional information about an individual’s pharmacogenetics may possibly facilitate the interpretation of the postmortem result and contribute to solve the “toxicological puzzle”.

The general aim of this thesis was to study if genetic variation in the drug metabolising enzymes, CYP2D6 and CYP2C19 can contribute to fatal intoxication. Reliable and rapid SNP and CNV assays suitable for forensic samples using PCR and pyrosequencing were developed for CYP2D6 and genotype frequencies in a Swedish population were shown to be in concordance with earlier published data. SNP assays were established for polymorphisms in the CYP2C19 gene.

Genotype distributions in fatal intoxication cases were compared with Swedish blood donors and significant difference between the materials were established. The allele CYP2D6*4 was found to be less frequent among the intoxication cases, as compared with the blood donors. No differences in CYP2C19 genotype frequencies were found between the materials. These findings are the opposite of our hypothesis that we expected to find an increased number of individuals carrying genetic variations, leading to poor metabolism among fatal intoxication cases. However, we are convinced that information concerning an individual’s genotype can be of importance in specific intoxication cases. Further studies are required to illuminate this question. Two further autopsy materials were studied; suicide cases (intoxications excluded) and natural death cases. A significant increased number of individuals carrying more than two active CYP2D6 alleles among the suicide cases were found compared to natural death cases. Furthermore, we found some significant differences between the materials when the individuals in each material were grouped according to how many active CYP2D6 alleles they carry in combination with the CYP2C19 genotype, which was divided into six subgroups. We do not currently have any explanation for the differences between the materials.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. p. 82
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1124
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17936 (URN)978-91-7393-639-2 (ISBN)
Public defence
2009-05-15, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-04-27 Created: 2009-04-27 Last updated: 2009-08-21Bibliographically approved
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