Matthaei, Johannes

[["dc.bibliographiccitation.journal","Frontiers in Pharmacology"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Klemp, Henry G."],["dc.contributor.author","Meyer, Marleen J."],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Tzvetkov, Mladen V."],["dc.date.accessioned","2021-07-05T14:57:56Z"],["dc.date.available","2021-07-05T14:57:56Z"],["dc.date.issued","2021"],["dc.description.abstract","Genome-wide association studies have identified an association between isobutyrylcarnitine (IBC) and organic cation transporter 1 (OCT1) genotypes. Higher IBC blood concentrations in humans with active OCT1 genotypes and experimental studies with mouse OCT1 suggested an OCT1-mediated efflux of IBC. In this study, we wanted to confirm the suggested use of IBC as an endogenous biomarker of OCT1 activity and contribute to a better understanding of the mechanisms behind the association between blood concentrations of carnitine derivatives and OCT1 genotype. Blood and urine IBC concentrations were quantified in healthy volunteers regarding intra- and interindividual variation and correlation with OCT1 genotype and with pharmacokinetics of known OCT1 substrates. Furthermore, IBC formation and transport were studied in cell lines overexpressing OCT1 and its naturally occurring variants. Carriers of high-activity OCT1 genotypes had about 3-fold higher IBC blood concentrations and 2-fold higher amounts of IBC excreted in urine compared to deficient OCT1. This was likely due to OCT1 function, as indicated by the fact that IBC correlated with the pharmacokinetics of known OCT1 substrates, like fenoterol, and blood IBC concentrations declined with a 1 h time delay following peak concentrations of the OCT1 substrate sumatriptan. Thus, IBC is a suitable endogenous biomarker reflecting both, human OCT1 (hOCT1) genotype and activity. While murine OCT1 (mOCT1) was an efflux transporter of IBC, hOCT1 exhibited no IBC efflux activity. Inhibition experiments confirmed this data showing that IBC and other acylcarnitines, like butyrylcarnitine, 2-methylbutyrylcarnitine, and hexanoylcarnitine, showed reduced efflux upon inhibition of mOCT1 but not of hOCT1. IBC and other carnitine derivatives are endogenous biomarkers of hOCT1 genotype and phenotype. However, in contrast to mice, the mechanisms underlying the IBC-OCT1 correlation in humans is apparently not directly the OCT1-mediated efflux of IBC. A plausible explanation could be that hOCT1 mediates cellular concentrations of specific regulators or co-substrates in lipid and energy metabolism, which is supported by our in vitro finding that at baseline intracellular IBC concentration is about 6-fold lower alone by OCT1 overexpression."],["dc.description.abstract","Genome-wide association studies have identified an association between isobutyrylcarnitine (IBC) and organic cation transporter 1 (OCT1) genotypes. Higher IBC blood concentrations in humans with active OCT1 genotypes and experimental studies with mouse OCT1 suggested an OCT1-mediated efflux of IBC. In this study, we wanted to confirm the suggested use of IBC as an endogenous biomarker of OCT1 activity and contribute to a better understanding of the mechanisms behind the association between blood concentrations of carnitine derivatives and OCT1 genotype. Blood and urine IBC concentrations were quantified in healthy volunteers regarding intra- and interindividual variation and correlation with OCT1 genotype and with pharmacokinetics of known OCT1 substrates. Furthermore, IBC formation and transport were studied in cell lines overexpressing OCT1 and its naturally occurring variants. Carriers of high-activity OCT1 genotypes had about 3-fold higher IBC blood concentrations and 2-fold higher amounts of IBC excreted in urine compared to deficient OCT1. This was likely due to OCT1 function, as indicated by the fact that IBC correlated with the pharmacokinetics of known OCT1 substrates, like fenoterol, and blood IBC concentrations declined with a 1 h time delay following peak concentrations of the OCT1 substrate sumatriptan. Thus, IBC is a suitable endogenous biomarker reflecting both, human OCT1 (hOCT1) genotype and activity. While murine OCT1 (mOCT1) was an efflux transporter of IBC, hOCT1 exhibited no IBC efflux activity. Inhibition experiments confirmed this data showing that IBC and other acylcarnitines, like butyrylcarnitine, 2-methylbutyrylcarnitine, and hexanoylcarnitine, showed reduced efflux upon inhibition of mOCT1 but not of hOCT1. IBC and other carnitine derivatives are endogenous biomarkers of hOCT1 genotype and phenotype. However, in contrast to mice, the mechanisms underlying the IBC-OCT1 correlation in humans is apparently not directly the OCT1-mediated efflux of IBC. A plausible explanation could be that hOCT1 mediates cellular concentrations of specific regulators or co-substrates in lipid and energy metabolism, which is supported by our in vitro finding that at baseline intracellular IBC concentration is about 6-fold lower alone by OCT1 overexpression."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.3389/fphar.2021.674559"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/87774"],["dc.notes.intern","DOI-Import GROB-441"],["dc.relation.eissn","1663-9812"],["dc.relation.orgunit","Institut für Klinische Pharmakologie"],["dc.rights","CC BY 4.0"],["dc.title","Isobutyrylcarnitine as a Biomarker of OCT1 Activity and Interspecies Differences in its Membrane Transport"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Pharmacology"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Römer, Sarah"],["dc.contributor.author","Meyer, Marleen J."],["dc.contributor.author","Klein, Kathrin"],["dc.contributor.author","Schneider, Lennart V."],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Tzvetkova, Ana"],["dc.contributor.author","Łapczuk-Romańska, Joanna"],["dc.contributor.author","Gaedcke, Jochen"],["dc.contributor.author","Droździk, Marek"],["dc.contributor.author","Tzvetkov, Mladen V."],["dc.date.accessioned","2021-07-05T14:57:56Z"],["dc.date.available","2021-07-05T14:57:56Z"],["dc.date.issued","2021"],["dc.description.abstract","Organic cation transporter 1 (OCT1, SLC22A1) is localized in the sinusoidal membrane of human hepatocytes and mediates hepatic uptake of weakly basic or cationic drugs and endogenous compounds. Common amino acid substitutions in OCT1 were associated with altered pharmacokinetics and efficacy of drugs like sumatriptan and fenoterol. Recently, the common splice variant rs35854239 has also been suggested to affect OCT1 function. rs35854239 represents an 8 bp duplication of the donor splice site at the exon 7-intron 7 junction. Here we quantified the extent to which this duplication affects OCT1 splicing and, as a consequence, the expression and the function of OCT1. We used pyrosequencing and deep RNA-sequencing to quantify the effect of rs35854239 on splicing after minigene expression of this variant in HepG2 and Huh7 cells and directly in human liver samples. Further, we analyzed the effects of rs35854239 on OCT1 mRNA expression in total, localization and activity of the resulting OCT1 protein, and on the pharmacokinetics of sumatriptan and fenoterol. The 8 bp duplication caused alternative splicing in 38% (deep RNA-sequencing) to 52% (pyrosequencing) of the minigene transcripts when analyzed in HepG2 and Huh7 cells. The alternatively spliced transcript encodes for a truncated protein that after transient transfection in HEK293 cells was not localized in the plasma membrane and was not able to transport the OCT1 model substrate ASP + . In human liver, however, the alternatively spliced OCT1 transcript was detectable only at very low levels (0.3% in heterozygous and 0.6% in homozygous carriers of the 8 bp duplication, deep RNA-sequencing). The 8 bp duplication was associated with a significant reduction of OCT1 expression in the human liver, but explained only 9% of the general variability in OCT1 expression and was not associated with significant changes in the pharmacokinetics of sumatriptan and fenoterol. Therefore, the rs35854239 variant only partially changes splicing, causing moderate changes in OCT1 expression and may be of only limited therapeutic relevance."],["dc.description.abstract","Organic cation transporter 1 (OCT1, SLC22A1) is localized in the sinusoidal membrane of human hepatocytes and mediates hepatic uptake of weakly basic or cationic drugs and endogenous compounds. Common amino acid substitutions in OCT1 were associated with altered pharmacokinetics and efficacy of drugs like sumatriptan and fenoterol. Recently, the common splice variant rs35854239 has also been suggested to affect OCT1 function. rs35854239 represents an 8 bp duplication of the donor splice site at the exon 7-intron 7 junction. Here we quantified the extent to which this duplication affects OCT1 splicing and, as a consequence, the expression and the function of OCT1. We used pyrosequencing and deep RNA-sequencing to quantify the effect of rs35854239 on splicing after minigene expression of this variant in HepG2 and Huh7 cells and directly in human liver samples. Further, we analyzed the effects of rs35854239 on OCT1 mRNA expression in total, localization and activity of the resulting OCT1 protein, and on the pharmacokinetics of sumatriptan and fenoterol. The 8 bp duplication caused alternative splicing in 38% (deep RNA-sequencing) to 52% (pyrosequencing) of the minigene transcripts when analyzed in HepG2 and Huh7 cells. The alternatively spliced transcript encodes for a truncated protein that after transient transfection in HEK293 cells was not localized in the plasma membrane and was not able to transport the OCT1 model substrate ASP + . In human liver, however, the alternatively spliced OCT1 transcript was detectable only at very low levels (0.3% in heterozygous and 0.6% in homozygous carriers of the 8 bp duplication, deep RNA-sequencing). The 8 bp duplication was associated with a significant reduction of OCT1 expression in the human liver, but explained only 9% of the general variability in OCT1 expression and was not associated with significant changes in the pharmacokinetics of sumatriptan and fenoterol. Therefore, the rs35854239 variant only partially changes splicing, causing moderate changes in OCT1 expression and may be of only limited therapeutic relevance."],["dc.identifier.doi","10.3389/fphar.2021.661480"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/87773"],["dc.notes.intern","DOI-Import GROB-441"],["dc.relation.eissn","1663-9812"],["dc.title","Effects of a Common Eight Base Pairs Duplication at the Exon 7-Intron 7 Junction on Splicing, Expression, and Function of OCT1"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Genetics"],["dc.bibliographiccitation.volume","11"],["dc.contributor.affiliation","Matthaei, Johannes; 1Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany"],["dc.contributor.affiliation","Bonat, Wagner Hugo; 2Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark"],["dc.contributor.affiliation","Kerb, Reinhold; 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany"],["dc.contributor.affiliation","Tzvetkov, Mladen Vassilev; 1Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany"],["dc.contributor.affiliation","Strube, Jakob; 1Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany"],["dc.contributor.affiliation","Brunke, Stefanie; 1Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany"],["dc.contributor.affiliation","Sachse-Seeboth, Cordula; 1Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany"],["dc.contributor.affiliation","Sehrt, Daniel; 1Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany"],["dc.contributor.affiliation","Hofmann, Ute; 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany"],["dc.contributor.affiliation","von Bornemann Hjelmborg, Jacob; 2Department of Epidemiology, Biostatistics and Biodemography, University of Southern Denmark, Odense, Denmark"],["dc.contributor.affiliation","Schwab, Matthias; 3Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, Stuttgart, Germany"],["dc.contributor.affiliation","Brockmöller, Jürgen; 1Institute for Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, Göttingen, Germany"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Bonat, Wagner Hugo"],["dc.contributor.author","Kerb, Reinhold"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.contributor.author","Strube, Jakob"],["dc.contributor.author","Brunke, Stefanie"],["dc.contributor.author","Sachse-Seeboth, Cordula"],["dc.contributor.author","Sehrt, Daniel"],["dc.contributor.author","Hofmann, Ute"],["dc.contributor.author","von Bornemann Hjelmborg, Jacob"],["dc.contributor.author","Schwab, Matthias"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.date.accessioned","2021-04-14T08:23:51Z"],["dc.date.available","2021-04-14T08:23:51Z"],["dc.date.issued","2020"],["dc.date.updated","2022-02-09T13:22:10Z"],["dc.description.abstract","Human CYP3A enzymes (including CYP3A4 and CYP4A5) metabolize about 40% of all drugs and numerous other environmental and endogenous substances. CYP3A activity is highly variable within and between humans. As a consequence, therapy with standard doses often results in too low or too high blood and tissue concentrations resulting in therapeutic failure or dose-related adverse reactions. It is an unanswered question how much of the big interindividual variation in CYP3A activity is caused by genetic or by environmental factors. This question can be answered by the twin study approach. Using midazolam as CYP3A probe drug, we studied 43 monozygotic and 14 dizygotic twins and measured midazolam and its metabolite 1-OH-midazolam. In addition, endogenous biomarkers of CYP3A activity, 4ß-OH-cholesterol and 6ß-OH-cortisol, were analyzed. Additive genetic effects accounted for only 15% of the variation in midazolam AUC, whereas 48% was attributed to common environmental factors. In contrast, 73, 56, and 31% of 1-OH-midazolam, 4ß-OH-cholesterol and 6ß-OH-cortisol variation was due to genetic effects. There was a low phenotypic correlation between the four CYP3A biomarkers. Only between midazolam and its 1-OH-metabolite, and between midazolam and 6ß-OH-cortisol we found significant bivariate genetic correlations. Midazolam AUC differed depending on the CYP3A4∗22 variant (p = 0.001) whereas plasma 4ß-OH-cholesterol was significantly lower in homozygous carriers of CYP3A5∗3 (p = 0.02). Apparently, non-genomic factors played a dominant role in the inter-individual variation of the CYP3A probe drug midazolam. A small intra-individual pharmacokinetic variation after repeated administration of midazolam was rated earlier as indication of high heritability of CYP3A activity, but according to present data that could also largely be due to constant environmental factors and/or heritability of liver blood flow. The higher heritabilities of 4ß-OH-cholesterol and of 1-OH-midazolam may deserve further research on the underlying factors beyond CYP3A genes. Clinical Trial Registration: ClinicalTrials.gov: NCT01845194 and EUDRA-CT: 2008-006223-31."],["dc.identifier.doi","10.3389/fgene.2020.00944"],["dc.identifier.eissn","1664-8021"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17521"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81074"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1664-8021"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","868"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Clinical Pharmacology & Therapeutics"],["dc.bibliographiccitation.lastpage","878"],["dc.bibliographiccitation.volume","103"],["dc.contributor.author","Tzvetkov, Mladen V."],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Pojar, Sherin"],["dc.contributor.author","Faltraco, Frank"],["dc.contributor.author","Vogler, Sabrina"],["dc.contributor.author","Prukop, Thomas"],["dc.contributor.author","Seitz, Tina"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.date.accessioned","2020-12-10T14:06:00Z"],["dc.date.available","2020-12-10T14:06:00Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1002/cpt.v103.5"],["dc.identifier.issn","0009-9236"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/69742"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","Increased Systemic Exposure and Stronger Cardiovascular and Metabolic Adverse Reactions to Fenoterol in Individuals with Heritable OCT1 Deficiency"],["dc.title.alternative","OCT1 deficiency and fenoterol toxicity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","628"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Clinical Pharmacology and Therapeutics"],["dc.bibliographiccitation.lastpage","638"],["dc.bibliographiccitation.volume","107"],["dc.contributor.affiliation","Matthaei, Johannes; 1Department of Clinical Pharmacology University Medical Center Georg August University Goettingen Germany"],["dc.contributor.affiliation","Blome, Felix; 1Department of Clinical Pharmacology University Medical Center Georg August University Goettingen Germany"],["dc.contributor.affiliation","Schwab, Matthias; 2Dr. Margarete Fischer‐Bosch Institute of Clinical Pharmacology University of Tübingen Stuttgart Germany"],["dc.contributor.affiliation","Tzvetkov, Mladen V.; 1Department of Clinical Pharmacology University Medical Center Georg August University Goettingen Germany"],["dc.contributor.affiliation","Brockmöller, Jürgen; 1Department of Clinical Pharmacology University Medical Center Georg August University Goettingen Germany"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Blome, Felix"],["dc.contributor.author","Schwab, Matthias"],["dc.contributor.author","Tzvetkov, Mladen V."],["dc.contributor.author","Brockmöller, Jürgen"],["dc.date.accessioned","2019-10-10T07:08:15Z"],["dc.date.available","2019-10-10T07:08:15Z"],["dc.date.issued","2019"],["dc.date.updated","2022-02-09T13:22:06Z"],["dc.description.abstract","Thiamine is substrate of the hepatic uptake transporter OCT1, and pathological lipid metabolism was associated with OCT1-dependent thiamine transport. But it is unknown whether clinical pharmacokinetics of thiamine is modulated by OCT1 genotype. We analyzed thiamine transport in vitro, thiamine blood concentrations after high-dose and low-dose (nutritional) intake, and heritability of thiamine and thiamine-phosphate blood concentrations. The variant OCT1 2 had reduced and OCT1 3 to OCT1 6 had deficient thiamine uptake activity. However, pharmacokinetics of thiamine did not differ depending on OCT1 genotype. Further studies in primary human hepatocytes indicated that several cation transporters including OCT1, OCT3, and THTR-2 contribute to hepatic uptake of thiamine. As much as 54% of the variation in thiamine and 75% in variation of thiamine monophosphate plasma concentrations was determined by heritable factors. Apparently thiamine is not useful as probe drug for OCT1 activity, but the high heritability particularly of thiamine monophosphate may stimulate further genomic research."],["dc.description.sponsorship","German Research Foundation (DFG)"],["dc.description.sponsorship","Robert Bosch Foundation http://dx.doi.org/10.13039/501100001646"],["dc.description.sponsorship","German Research Foundation under Germany's Excellence Strategy"],["dc.identifier.doi","10.1002/cpt.1666"],["dc.identifier.pmid","31593619"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17025"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/62482"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.eissn","1532-6535"],["dc.relation.issn","0009-9236"],["dc.relation.issn","1532-6535"],["dc.rights","CC BY-NC-ND 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc-nd/4.0"],["dc.title","Variability and heritability of thiamine pharmacokinetics with focus on OCT1 effects on membrane transport and pharmacokinetics in humans"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","633"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Clinical Pharmacology & Therapeutics"],["dc.bibliographiccitation.lastpage","641"],["dc.bibliographiccitation.volume","99"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Kuron, D."],["dc.contributor.author","Faltraco, F."],["dc.contributor.author","Knoch, T."],["dc.contributor.author","Pereira, J. N. Dos Santos"],["dc.contributor.author","Abu Abed, Manar"],["dc.contributor.author","Prukop, Thomas"],["dc.contributor.author","Brockmoeller, Juergen"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.date.accessioned","2018-11-07T10:13:49Z"],["dc.date.available","2018-11-07T10:13:49Z"],["dc.date.issued","2016"],["dc.description.abstract","The low bioavailability of the anti-migraine drug sumatriptan is partially caused by first-pass hepatic metabolism. In this study, we analyzed the impact of the hepatic organic cation transporter OCT1 on sumatriptan cellular uptake, and of OCT1 polymorphisms on sumatriptan pharmacokinetics. OCT1 transported sumatriptan with high capacity and sumatriptan uptake into human hepatocytes was strongly inhibited by the OCT1 inhibitor MPP+. Sumatriptan uptake was not affected by the Met420del polymorphism, but was strongly reduced by Arg61Cys and Gly401Ser, and completely abolished by Gly465Arg and Cys88Arg. Plasma concentrations in humans with two deficient OCT1 alleles were 215% of those with fully active OCT1 (P = 0.0003). OCT1 also transported naratriptan, rizatriptan, and zolmitriptan, suggesting a possible impact of OCT1 polymorphisms on the pharmacokinetics of other triptans as well. In conclusion, OCT1 is a high-capacity transporter of sumatriptan and polymorphisms causing OCT1 deficiency have similar effects on sumatriptan pharmacokinetics as those observed in subjects with liver impairment."],["dc.description.sponsorship","German Research Foundation (DFG) [TZ 74/1-1]"],["dc.identifier.doi","10.1002/cpt.317"],["dc.identifier.isi","000376246600022"],["dc.identifier.pmid","26659468"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40504"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Wiley-blackwell"],["dc.relation.issn","1532-6535"],["dc.relation.issn","0009-9236"],["dc.title","OCT1 Mediates Hepatic Uptake of Sumatriptan and Loss-of-Function OCT1 Polymorphisms Affect Sumatriptan Pharmacokinetics"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1002286"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","PLoS Medicine"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Schütz, Ekkehard"],["dc.contributor.author","Fischer, Anna"],["dc.contributor.author","Beck, Julia"],["dc.contributor.author","Harden, Markus"],["dc.contributor.author","Koch, Martina"],["dc.contributor.author","Wuensch, Tilo"],["dc.contributor.author","Stockmann, Martin"],["dc.contributor.author","Nashan, Bjoern"],["dc.contributor.author","Kollmar, Otto"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Kanzow, Philipp"],["dc.contributor.author","Walson, Philip D."],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Oellerich, Michael"],["dc.date.accessioned","2018-11-07T10:25:24Z"],["dc.date.accessioned","2020-05-22T07:30:58Z"],["dc.date.available","2018-11-07T10:25:24Z"],["dc.date.available","2020-05-22T07:30:58Z"],["dc.date.issued","2017"],["dc.description.abstract","Background Graft-derived cell-free DNA (GcfDNA), which is released into the blood stream by necrotic and apoptotic cells, is a promising noninvasive organ integrity biomarker. In liver transplantation (LTx), neither conventional liver function tests (LTFs) nor immunosuppressive drug monitoring are very effective for rejection monitoring. We therefore hypothesized that the quantitative measurement of donor-derived cell-free DNA (cfDNA) would have independent value for the assessment of graft integrity, including damage from acute rejection. Methods and findings Traditional LFTs were performed and plasma GcfDNA was monitored in 115 adults post-LTx at three German transplant centers as part of a prospective, observational, multicenter cohort trial. GcfDNA percentage (graft cfDNA/total cfDNA) was measured using droplet digital PCR (ddPCR), based on a limited number of predefined single nucleotide polymorphisms, enabling same-day turn-around. The same method was used to quantify blood microchimerism. GcfDNA was increased >50% on day 1 post-LTx, presumably from ischemia/reperfusion damage, but rapidly declined in patients without graft injury within 7 to 10 d to a median <10%, where it remained for the 1-y observation period. Of 115 patients, 107 provided samples that met preestablished criteria. In 31 samples taken from 17 patients during biopsy-proven acute rejection episodes, the percentage of GcfDNA was elevated substantially (median 29.6%, 95% CI 23.6%-41.0%) compared with that in 282 samples from 88 patients during stable periods (median 3.3%, 95% CI 2.9%-3.7%; p < 0.001). Only slightly higher values (median 5.9%, 95% CI 4.4%-10.3%) were found in 68 samples from 17 hepatitis C virus (HCV)-positive, rejection-free patients. LFTs had low overall correlations (r = 0.28-0.62) with GcfDNA and showed greater overlap between patient subgroups, especially between acute rejection and HCV+ patients. Multivariable logistic regression modeling demonstrated that GcfDNA provided additional LFT-independent information on graft integrity. Diagnostic sensitivity and specificity were 90.3% (95% CI 74.2%-98.0%) and 92.9% (95% CI 89.3%-95.6%), respectively, for GcfDNA at a threshold value of 10%. The area under the receiver operator characteristic curve was higher for GcfDNA (97.1%, 95% CI 93.4%-100%) than for same-day conventional LFTs (AST: 95.7%; ALT: 95.2%; gamma-GT: 94.5%; bilirubin: 82.6%). An evaluation of microchimerism revealed that the maximum donor DNA in circulating white blood cells was only 0.068%. GcfDNA percentage can be influenced by major changes in host cfDNA (e.g., due to leukopenia or leukocytosis). One limitation of our study is that exact time-matched GcfDNA and LFT samples were not available for all patient visits. Conclusions In this study, determination of GcfDNA in plasma by ddPCR allowed for earlier and more sensitive discrimination of acute rejection in LTx patients as compared with conventional LFTs. Potential blood microchimerism was quantitatively low and had no significant influence on GcfDNA value. Further research, which should ideally include protocol biopsies, will be needed to establish the practical value of GcfDNA measurements in the management of LTx patients."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2017"],["dc.identifier.doi","10.1371/journal.pmed.1002286"],["dc.identifier.isi","000400768500015"],["dc.identifier.pmid","28441386"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14418"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42852"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/65693"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","1549-1676"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: A prospective, observational, multicenter cohort study"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Naunyn-Schmiedeberg s Archives of Pharmacology"],["dc.bibliographiccitation.volume","388"],["dc.contributor.author","Kuron, D."],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Brockmoeller, Juergen"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.date.accessioned","2018-11-07T10:01:09Z"],["dc.date.available","2018-11-07T10:01:09Z"],["dc.date.issued","2015"],["dc.format.extent","S54"],["dc.identifier.isi","000359539100219"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/37953"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.publisher.place","New york"],["dc.relation.conference","81st Annual Meeting of the Deutsche-Gesellschaft-fur-Experimentelle-und-Klinische-Pharmakologie-und Toxikologie-e-V"],["dc.relation.eventlocation","Kiel, GERMANY"],["dc.relation.issn","1432-1912"],["dc.relation.issn","0028-1298"],["dc.title","OCT1 is the clinically relevant hepatic transporter of sumatriptan: in vitro and in vivo evidences"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","119"],["dc.bibliographiccitation.journal","Genome Medicine"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.contributor.author","Gal, Valerie"],["dc.contributor.author","Sachse-Seeboth, Cordula"],["dc.contributor.author","Sehrt, Daniel"],["dc.contributor.author","Hjelmborg, Jakob B."],["dc.contributor.author","Hofmann, Ute"],["dc.contributor.author","Schwab, Matthias"],["dc.contributor.author","Kerb, Reinhold"],["dc.contributor.author","Brockmoeller, Juergen"],["dc.date.accessioned","2018-11-07T10:05:52Z"],["dc.date.available","2018-11-07T10:05:52Z"],["dc.date.issued","2016"],["dc.description.abstract","Background: Efflux transporters like MDR1 and MRP2 may modulate the pharmacokinetics of about 50 % of all drugs. It is currently unknown how much of the variation in the activities of important drug membrane transporters like MDR1 or MRP2 is determined by genetic or by environmental factors. In this study we assessed the heritability of the pharmacokinetics of talinolol as a putative probe drug for MDR1 and possibly other membrane transporters. Methods: Talinolol pharmacokinetics were investigated in a repeated dose study in 42 monozygotic and 13 same-sex dizygotic twin pairs. The oral clearance of talinolol was predefined as the primary parameter. Heritability was analyzed by structural equation modeling and by within-and between-subject variance and talinolol clearance was correlated with polymorphisms in MDR1, MRP2, BCRP, MDR5, OATP1B1, and OCT1. Results: Talinolol clearance varied approximately ninefold in the studied sample of healthy volunteers. The correlation of clearances between siblings was not significantly different for the monozygotic and dizygotic pairs. All data analyses consistently showed that variation of talinolol pharmacokinetics was mainly determined by environmental effects. Structural equation modeling attributed 53.5 % of the variation of oral clearance to common environmental effects influencing both siblings to the same extent and 46.5 % to unique environmental effects randomly affecting individual subjects. Talinolol pharmacokinetics were significantly dependent on sex, body mass index, total protein consumption, and vegetable consumption. Conclusions: The twin study revealed that environmental factors explained much more of the variation in pharmacokinetics of talinolol than genetic factors."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2016"],["dc.identifier.doi","10.1186/s13073-016-0372-2"],["dc.identifier.isi","000387622000001"],["dc.identifier.pmid","27825374"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13910"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/38984"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Biomed Central Ltd"],["dc.relation.issn","1756-994X"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Low heritability in pharmacokinetics of talinolol: a pharmacogenetic twin study on the heritability of the pharmacokinetics of talinolol, a putative probe drug of MDR1 and other membrane transporters"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","611"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Clinical Pharmacology & Therapeutics"],["dc.bibliographiccitation.lastpage","621"],["dc.bibliographiccitation.volume","98"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.contributor.author","Sehrt, Daniel"],["dc.contributor.author","Sachse-Seeboth, Cordula"],["dc.contributor.author","Hjelmborg, Jakob B."],["dc.contributor.author","Möller, S."],["dc.contributor.author","Halekoh, U."],["dc.contributor.author","Hofmann, U. G."],["dc.contributor.author","Schwab, M."],["dc.contributor.author","Kerb, Reinhold"],["dc.date.accessioned","2018-11-07T09:47:56Z"],["dc.date.available","2018-11-07T09:47:56Z"],["dc.date.issued","2015"],["dc.description.abstract","Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated."],["dc.identifier.doi","10.1002/cpt.258"],["dc.identifier.isi","000368692200016"],["dc.identifier.pmid","26344676"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/35203"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.issn","1532-6535"],["dc.relation.issn","0009-9236"],["dc.title","Heritability of Metoprolol and Torsemide Pharmacokinetics"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]