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Josefsson, Martin
Publications (10 of 23) Show all publications
Haage, P., Kronstrand, R., Josefsson, M., Calistri, S., van Schaik, R. H., Green, H. & Kugelberg, F. (2018). Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype. Pharmacology Research & Perspectives, 6(4), Article ID e00419.
Open this publication in new window or tab >>Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype
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2018 (English)In: Pharmacology Research & Perspectives, ISSN 2052-1707, Vol. 6, no 4, article id e00419Article in journal (Refereed) Published
Abstract [en]

Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC-MS/MS and the CYP2D6,CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real-time PCR, respectively. A positive correlation between the (+)/(-)-enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N-desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N-desmethyltramadol enantiomers and low corresponding values of the O-desmethyltramadol and N,O-didesmethyltramadol enantiomers, especially of the (+)-enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)-O-desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(-)-enantiomer ratio of O-desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-152586 (URN)10.1002/prp2.419 (DOI)000442994300006 ()29992026 (PubMedID)2-s2.0-85052511964 (Scopus ID)
Available from: 2018-11-09 Created: 2018-11-09 Last updated: 2018-12-03Bibliographically approved
Vikingsson, S., Gréen, H., Brinkhagen, L., Mukhtar, S. & Josefsson, M. (2016). Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry.. Drug Testing and Analysis, 8(9), 950-956
Open this publication in new window or tab >>Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry.
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2016 (English)In: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 8, no 9, p. 950-956Article in journal (Refereed) Published
Abstract [en]

Synthetic cannabinoids are a group of psychoactive drugs presently widespread among drug users in Europe. Analytical methods to measure these compounds in urine are in demand as urine is a preferred matrix for drug testing. For most synthetic cannabinoids, the parent compounds are rarely detected in urine. Therefore urinary metabolites are needed as markers of drug intake. AB-FUBINACA was one of the top three synthetic cannabinoids most frequently found in seizures and toxicological drug screening in Sweden (2013-2014). Drug abuse is also reported from several other countries such as the USA and Japan. In this study, 28 authentic case samples were used to identify urinary markers of AB-FUBINACA intake using liquid chromatography quadrupole tandem time of flight mass spectrometry and human liver microsomes. Three metabolites suitable as markers of drug intake were identified and at least two of them were detected in all but one case. In total, 15 urinary metabolites of AB-FUBINACA were reported, including hydrolxylations on the indazole ring and the amino-oxobutane moiety, dealkylations and hydrolysis of the primary amide. No modifications on the fluorobenzyl side-chain were observed. The parent compound was detected in 54% of the case samples. Also, after three hours of incubation with human liver microsomes, 77% of the signal from the parent compound remained. Copyright © 2015 John Wiley & Sons, Ltd.

Keywords
LC-MS/MS; Spice; drugs of abuse; human liver microsomes; metabolites; new psychoactive substances; synthetic cannabinoids; urine
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:liu:diva-125343 (URN)10.1002/dta.1896 (DOI)000384805600007 ()26560240 (PubMedID)
Note

Funding agencies: National Board of Forensic Medicine; Linkoping University; Linkoping physician society; Swedish Civil Contingencies Agency

Available from: 2016-02-19 Created: 2016-02-19 Last updated: 2018-01-10
Haage, P., Kronstrand, R., Carlsson, B. & Josefsson, M. (2016). Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.. Journal of Pharmaceutical and Biomedical Analysis, 119, 1-9
Open this publication in new window or tab >>Quantitation of the enantiomers of tramadol and its three main metabolites in human whole blood using LC-MS/MS.
2016 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 119, p. 1-9Article in journal (Refereed) Published
Abstract [en]

The analgesic drug tramadol and its metabolites are chiral compounds, with the (+)- and (-)-enantiomers showing different pharmacological and toxicological effects. This novel enantioselective method, based on LC-MS/MS in reversed phase mode, enabled measurement of the parent compound and its three main metabolites O-desmethyltramadol, N-desmethyltramadol and N,O-didesmethyltramadol simultaneously. Whole blood samples of 0.5g were fortified with internal standards (tramadol-(13)C-D3 and O-desmethyl-cis-tramadol-D6) and extracted under basic conditions (pH 11) by liquid-liquid extraction. Chromatography was performed on a chiral alpha-1-acid glycoprotein (AGP) column preceded by an AGP guard column. The mobile phase consisted of 0.8% acetonitrile and 99.2% ammonium acetate (20mM, pH 7.2). A post-column infusion with 0.05% formic acid in acetonitrile was used to enhance sensitivity. Quantitation as well as enantiomeric ratio measurements were covered by quality controls. Validation parameters for all eight enantiomers included selectivity (high), matrix effects (no ion suppression/enhancement), calibration model (linear, weight 1/X(2), in the range of 0.25-250ng/g), limit of quantitation (0.125-0.50ng/g), repeatability (2-6%) and intermediate precision (2-7%), accuracy (83-114%), dilution integrity (98-115%), carry over (not exceeding 0.07%) and stability (stable in blood and extract). The method was applied to blood samples from a healthy volunteer administrated a single 100mg dose and to a case sample concerning an impaired driver, which confirmed its applicability in human pharmacokinetic studies as well as in toxicological and forensic investigations.

Keywords
Enantiomer; LC–MS/MS; N, O-didesmethyltramadol; N-desmethyltramadol; O-desmethyltramadol; Tramadol
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:liu:diva-125284 (URN)10.1016/j.jpba.2015.11.012 (DOI)000370211900001 ()26625281 (PubMedID)
Note

Funding agencies:The National Board of Forensic Medicine in Sweden funded this work.

Available from: 2016-02-19 Created: 2016-02-19 Last updated: 2018-11-09
Vikingsson, S., Josefsson, M. & Green, H. (2015). Identification of AKB-48 and 5F-AKB-48 Metabolites in Authentic Human Urine Samples Using Human Liver Microsomes and Time of Flight Mass Spectrometry. Journal of Analytical Toxicology, 39(6), 426-435
Open this publication in new window or tab >>Identification of AKB-48 and 5F-AKB-48 Metabolites in Authentic Human Urine Samples Using Human Liver Microsomes and Time of Flight Mass Spectrometry
2015 (English)In: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 39, no 6, p. 426-435Article in journal (Refereed) Published
Abstract [en]

The occurrence of structurally related synthetic cannabinoids makes the identification of unique markers of drug intake particularly challenging. The aim of this study was to identify unique and abundant metabolites of AKB-48 and 5F-AKB-48 for toxicological screening in urine. Investigations of authentic urine samples from forensic cases in combination with human liver microsome (HLM) experiments were used for identification of metabolites. HLM incubations of AKB-48 and 5F-AKB-48 along with 35 urine samples from authentic cases were analyzed with liquid chromatography quadrupole tandem time of flight mass spectrometry. Using HLMs 41 metabolites of AKB-48 and 37 metabolites of 5F-AKB-48 were identified, principally represented by hydroxylation but also ketone formation and dealkylation. Monohydroxylated metabolites were replaced by di- and trihydroxylated metabolites within 30 min. The metabolites from the HLM incubations accounted for on average 84% (range, 67-100) and 91% (range, 71-100) of the combined area in the case samples for AKB-48 and 5F-AKB-48, respectively. While defluorinated metabolites accounted for on average 74% of the combined area after a 5F-AKB-48 intake only a few identified metabolites were shared between AKB-48 and 5F-AKB-48, illustrating the need for a systematic approach to identify unique metabolites. HLMs in combination with case samples seem suitable for this purpose.

Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy F, 2015
National Category
Clinical Medicine Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-121141 (URN)10.1093/jat/bkv045 (DOI)000359730100002 ()25957385 (PubMedID)
Note

Funding Agencies|National Board of Forensic Medicine; Linkoping University; Swedish Civil Contingencies Agency

Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2017-12-04
Kronstrand, R., Brinkhagen, L., Birath-Karlsson, C., Roman, M. & Josefsson, M. (2014). LC-QTOF-MS as a superior strategy to immunoassay for the comprehensive analysis of synthetic cannabinoids in urine. Analytical and Bioanalytical Chemistry, 406(15), 3599-3609
Open this publication in new window or tab >>LC-QTOF-MS as a superior strategy to immunoassay for the comprehensive analysis of synthetic cannabinoids in urine
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2014 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 406, no 15, p. 3599-3609Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to compare the performance of an immunoassay screening for synthetic cannabinoids with a newly developed confirmation method using liquid chromatography quadrupole time-of-flight mass spectrometry. The screening included metabolites from JWH-018, JWH-073, and AM-2201. The confirmation included metabolites from AM-2201, JWH-018, JWH-019, JWH-073, JWH-081, JWH-122, JWH-210, JWH-250, JWH-398, MAM-2201, RCS-4, and UR-144. The immunoassay was tested and found to have no cross-reactivity with UR-144 metabolites but considerable cross-reactivity with MAM-2201 and JWH-122 metabolites. Sensitivity and specificity for the immunoassay were evaluated with 87 authentic urine samples and found to be 87 % and 82 %, respectively. With a cutoff at 2 ng/ml, the confirmation showed 80 positive findings in 38 cases. The most common finding was JWH-122 5-OH-pentyl, followed by JWH-018 5-OH-pentyl. There were 9 findings of UR-144 metabolites and 3 of JWH-073 metabolites. In summary, the immunoassay performed well, presenting both high sensitivity and specificity for the synthetic cannabinoids present in the urine samples tested. The rapid exchange of one cannabinoid for another may pose problems for immunoassays as well as for confirmation methods. However, we consider time-of-flight mass spectrometry to be superior since new metabolites can be quickly included and identified.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2014
Keywords
LC-Q-TOF; Synthetic cannabinoids; Immunoassay; Metabolites; Forensic
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-107824 (URN)10.1007/s00216-013-7574-x (DOI)000336393900008 ()
Available from: 2014-06-23 Created: 2014-06-23 Last updated: 2017-12-05
Roman, M., Strom, L., Tell, H. & Josefsson, M. (2013). Liquid chromatography/time-of-flight mass spectrometry analysis of postmortem blood samples for targeted toxicological screening. Analytical and Bioanalytical Chemistry, 405(12), 4107-4125
Open this publication in new window or tab >>Liquid chromatography/time-of-flight mass spectrometry analysis of postmortem blood samples for targeted toxicological screening
2013 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 405, no 12, p. 4107-4125Article in journal (Refereed) Published
Abstract [en]

A liquid chromatography/time-of-flight mass spectrometry (LC-TOF-MS) method for targeted toxicological screening in human postmortem blood samples from forensic autopsy cases has been developed, validated and compared with a previously used method using gas chromatography with nitrogen-phosphorus detection (GC-NPD). Separation was achieved within 12 min by high-resolution gradient chromatography. Ions were generated in positive and negative electrospray ionization mode and were detected in 2-GHz single mass spectrometry mode, m/z range 50-1,000. Before injection, 0.25 g blood was prepared by protein precipitation with 500 mu L of a mixture of acetonitrile and ethanol containing deuterated internal standards. An in-house database comprising 240 drugs and metabolites was built by analysing solutions from certified standards or other documented reference material available. Identification was based on scoring of retention time, accurate mass measurement and isotopic pattern. Validation was performed on spiked blood samples and authentic postmortem blood samples. The thresholds defined as minimum required performance levels were for most compounds in the range from 0.01 to 0.10 mu g/g. Typically, a mass error of less than 2 ppm and a precision of area measurements of less than 5 % coefficient of variation were achieved. Positive identification was confirmed at concentrations up to 500 mu g/g. Most compounds were determined in positive ionization mode, but for a limited number of compounds (fewer than 4 %) negative ionization was needed and a few early-eluted compounds could not be identified owing to substantial influence of interferences from the matrix and were thus not included in the screening. A robust and valid toxicological screening by LC-TOF-MS for postmortem blood samples, covering 50 % more compounds, and with higher precision and sensitivity than the previously used screening by GC-NPD was achieved.

Place, publisher, year, edition, pages
Springer Verlag (Germany), 2013
Keywords
Postmortem, Blood, Liquid chromatography, Mass spectrometry, Time of flight, Liquid chromatography/time-of-flight mass spectrometry
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-93975 (URN)10.1007/s00216-013-6798-0 (DOI)000317643900023 ()
Available from: 2013-06-13 Created: 2013-06-13 Last updated: 2017-12-06
Vikingsson, S., Almer, S., Peterson, C., Carlsson, B. & Josefsson, M. (2013). Monitoring of thiopurine metabolites - A high-performance liquid chromatography method for clinical use. Journal of Pharmaceutical and Biomedical Analysis, 75, 145-152
Open this publication in new window or tab >>Monitoring of thiopurine metabolites - A high-performance liquid chromatography method for clinical use
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2013 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 75, p. 145-152Article in journal (Refereed) Published
Abstract [en]

A high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBCs were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials. Ten patient samples were analysed to demonstrate clinical application and to establish pilot ranges for all analytes. less thanbrgreater than less thanbrgreater thanThe method measured thioguanosine mono-(TGMP), di-(TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine). less thanbrgreater than less thanbrgreater thanLOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8 x 10(8) RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 4 degrees C for 8 h after sampling.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Inflammatory bowel disease (IBD), HPLC, Nucleotide, Acute lymphoid leukaemia, Pharmacogenetics
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-89732 (URN)10.1016/j.jpba.2012.11.027 (DOI)000314332500019 ()
Note

Funding Agencies|Swedish Cancer Society||Swedish Childhood Cancer Foundation||Swedish Medical Research Council||

Available from: 2013-03-05 Created: 2013-03-05 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
Josefsson, M. & Rydberg, I. (2011). Determination of methylphenidate and ritalinic acid in blood, plasma and oral fluid from adolescents and adults using protein precipitation and liquid chromatography tandem mass spectrometry-A method applied on clinical and forensic investigations. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 55(5), 1050-1059
Open this publication in new window or tab >>Determination of methylphenidate and ritalinic acid in blood, plasma and oral fluid from adolescents and adults using protein precipitation and liquid chromatography tandem mass spectrometry-A method applied on clinical and forensic investigations
2011 (English)In: JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, ISSN 0731-7085, Vol. 55, no 5, p. 1050-1059Article in journal (Refereed) Published
Abstract [en]

A validated, accurate and sensitive LC-MS/MS method for determination of racemic methylphenidate and its metabolite ritalinic acid has been developed. The analytes were quantified by tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring. Blood, plasma and oral fluid samples of 100 mu l were prepared by simple precipitation with 200 RI of an aqueous solution of zinc sulphate in methanol. Corresponding deuterated internal standards were used for quantification. Calibrations for methylphenidate and ritalinic acid were linear within the selected range of 0.2-30 ng/ml and 10-1500 ng/ml in blood or plasma and in the range of 1-500 ng/ml and 0.25-125 ng/ml in oral fluid, respectively. The method was successfully applied for the analysis of samples from patients treated with methylphenidate in the dose range of 36-72 mg/day and some representative ante mortem and post mortem samples from clinical and forensic toxicological investigations. A three to fourfold higher concentration of methylphenidate was found in oral fluid compared with blood while for ritalinic acid the concentrations were about 25-fold lower in oral fluid.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2011
Keywords
Methylphenidate, Ritalinic acid, Blood, Oral fluid, LC-MS/MS
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69174 (URN)10.1016/j.jpba.2011.03.009 (DOI)000291129700023 ()
Available from: 2011-06-17 Created: 2011-06-17 Last updated: 2011-06-17
Skogh, E., Sjödin, I., Josefsson, M. & Dahl, M.-L. (2011). High Correlation Between Serum and Cerebrospinal Fluid Olanzapine Concentrations in Patients With Schizophrenia or Schizoaffective Disorder Medicating With Oral Olanzapine as the Only Antipsychotic Drug. Journal of Clinical Psychopharmacology, 31(1), 4-9
Open this publication in new window or tab >>High Correlation Between Serum and Cerebrospinal Fluid Olanzapine Concentrations in Patients With Schizophrenia or Schizoaffective Disorder Medicating With Oral Olanzapine as the Only Antipsychotic Drug
2011 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 31, no 1, p. 4-9Article in journal (Refereed) Published
Abstract [en]

The primary aim of the present study was to investigate the relationship between steady state serum and cerebrospinal fluid (CSF) concentrations of olanzapine (OLA) and its metabolite 4-N-desmethylolanzapine (DMO) in patients with schizophrenia or schizoaffective disorder treated with oral OLA as the only antipsychotic drug. The influence of smoking, gender, age, as well as polymorphisms in cytochrome P450 CYP2D6, CYP1A2, and ABCB1 genes on the serum and CSF drug levels was also analyzed. Thirty-seven white outpatients (10 smokers and 27 nonsmokers) were included. From 29 of them, CSF was collected successfully. A strong correlation (Spearman rank correlation [r(s)] = 0.93; P = 0.05) was found between serum and CSF concentrations of OLA and a somewhat weaker correlation (r(s) = 0.5; P = 0.05) between those of DMO. The CSF concentrations of OLA and DMO were on average 12% and 16% of those in serum. Extensive metabolizers of CYP2D6 had higher (P = 0.05) daily doses than poor metabolizers when the influence of smoking was taken into account. Smokers had lower (P = 0.01) concentration-to-dose ratios of OLA in serum (mean, 2.23 ng/mL per mg vs 3.32 ng/mL per mg) and CSF (0.27 ng/mL per mg vs 0.41 ng/mL per mg) than nonsmokers. The concentration-to-dose ratio for serum DMO decreased with increasing age (r(s) = -0.41; P = 0.05). Carriers of ABCB1 1236T/2677T/3435T haplotype had higher serum (mean, 37.7 ng/mL vs 22.5 ng/mL; P = 0.035) and CSF (4.7 ng/mL vs 2.6 ng/mL; P = 0.018) OLA concentrations than patients without this haplotype. The present study shows a strong correlation between serum and CSF concentrations of OLA, indicating that concentrations of OLA in serum reflect those in CSF.

Place, publisher, year, edition, pages
Williams and Wilkins, 2011
Keywords
olanzapine, smoking, serum concentration, cerebrospinal fluid, pharmacogenetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-64762 (URN)10.1097/JCP.0b013e318204d9e2 (DOI)000285771000002 ()
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2017-12-11Bibliographically approved
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