Matthaei, Johannes

[["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.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","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.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.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"]]

[["dc.bibliographiccitation.firstpage","190"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Clinical Pharmacology and Therapeutics"],["dc.bibliographiccitation.lastpage","200"],["dc.bibliographiccitation.volume","105"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Seitz, Tina"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Tann, Annabelle"],["dc.contributor.author","Prukop, Thomas"],["dc.contributor.author","Tadjerpisheh, Sina"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Tzvetkov, Mladen V."],["dc.date.accessioned","2019-10-10T07:11:32Z"],["dc.date.available","2019-10-10T07:11:32Z"],["dc.date.issued","2019"],["dc.description.abstract","Cycloguanil, the active metabolite of proguanil, acts on malaria schizonts in erythrocytes and hepatocytes. We analyzed the impact of the organic cation transporter OCT1 on hepatocellular uptake and pharmacokinetics of proguanil and cycloguanil. OCT1 transported both proguanil and cycloguanil. Common variants OCT1 3 and OCT1 4 caused a substantial decrease and OCT1 5 and OCT1 6 complete abolishment of proguanil uptake. In 39 healthy subjects, low-activity variants OCT1 3 and OCT1 4 had only minor effects on proguanil pharmacokinetics. However, both, cycloguanil area under the time-concentration curve and the cycloguanil-to-proguanil ratio were significantly dependent on number of these low-functional alleles (P = 0.02 for both). Together, CYP2C19, CYP3A5, OCT1 polymorphisms, and sex accounted for 61% of the variation in the cycloguanil-to-proguanil ratio. Most importantly, in vitro OCT1 inhibition caused a fivefold decrease of intracellular cycloguanil concentrations in primary human hepatocytes. In conclusion, OCT1-mediated uptake is a limiting step in bioactivation of proguanil, and OCT1 polymorphisms may affect proguanil efficacy against hepatic malaria schizonts."],["dc.identifier.doi","10.1002/cpt.1128"],["dc.identifier.pmid","29882324"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/62483"],["dc.language.iso","en"],["dc.relation.eissn","1532-6535"],["dc.relation.issn","0009-9236"],["dc.title","OCT1 Deficiency Affects Hepatocellular Concentrations and Pharmacokinetics of Cycloguanil, the Active Metabolite of the Antimalarial Drug Proguanil"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]