Jensen, Ole

[["dc.bibliographiccitation.artnumber","70"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Journal of Clinical Medicine"],["dc.bibliographiccitation.volume","8"],["dc.contributor.affiliation","Mewes, Caspar; \t\t \r\n\t\t Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany,"],["dc.contributor.affiliation","Büttner, Benedikt; \t\t \r\n\t\t Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany,"],["dc.contributor.affiliation","Hinz, José; \t\t \r\n\t\t Department of Anesthesiology and Intensive Care Medicine, Klinikum Region Hannover, D-30459 Hannover, Germany,"],["dc.contributor.affiliation","Alpert, Ayelet; \t\t \r\n\t\t Faculty of Medicine, Technion−Israeli Institute of Technology, 31096 Haifa, Israel,"],["dc.contributor.affiliation","Popov, Aron-Frederik; \t\t \r\n\t\t Department of Thoracic and Cardiovascular Surgery, University Medical Center, Eberhard Karls University, D-72076 Tuebingen, Germany,"],["dc.contributor.affiliation","Ghadimi, Michael; \t\t \r\n\t\t Department of General and Visceral Surgery, University Medical Center, Georg August University, D-37075 Goettingen, Germany,"],["dc.contributor.affiliation","Beissbarth, Tim; \t\t \r\n\t\t Department of Medical Bioinformatics, University Medical Center, Georg August University, D-37077 Goettingen, Germany,"],["dc.contributor.affiliation","Tzvetkov, Mladen; \t\t \r\n\t\t Department of Pharmacology, University Medical Center, Ernst-Moritz-Arndt-University, D-17487 Greifswald, Germany,"],["dc.contributor.affiliation","Jensen, Ole; \t\t \r\n\t\t Department of Clinical Pharmacology, University Medical Center, Georg August University, D-37075 Goettingen, Germany,"],["dc.contributor.affiliation","Runzheimer, Julius; \t\t \r\n\t\t Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany,"],["dc.contributor.affiliation","Quintel, Michael; \t\t \r\n\t\t Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany,"],["dc.contributor.affiliation","Shen-Orr, Shai; \t\t \r\n\t\t Faculty of Medicine, Technion−Israeli Institute of Technology, 31096 Haifa, Israel,"],["dc.contributor.affiliation","Bergmann, Ingo; \t\t \r\n\t\t Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany,"],["dc.contributor.affiliation","Mansur, Ashham; \t\t \r\n\t\t Department of Anesthesiology, University Medical Center, Georg August University, D-37075 Goettingen, Germany,"],["dc.contributor.author","Mewes, Caspar"],["dc.contributor.author","Büttner, Benedikt"],["dc.contributor.author","Hinz, José Maria"],["dc.contributor.author","Alpert, Ayelet"],["dc.contributor.author","Popov, Aron-Frederik"],["dc.contributor.author","Ghadimi, Michael B."],["dc.contributor.author","Beißbarth, Tim"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Runzheimer, Julius"],["dc.contributor.author","Quintel, Michael I."],["dc.contributor.author","Shen-Orr, Shai"],["dc.contributor.author","Bergmann, Ingo"],["dc.contributor.author","Mansur, Ashham"],["dc.date.accessioned","2019-07-09T11:49:58Z"],["dc.date.available","2019-07-09T11:49:58Z"],["dc.date.issued","2019"],["dc.date.updated","2022-02-09T13:23:19Z"],["dc.description.abstract","Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a coinhibitory checkpoint protein expressed on the surface of T cells. A recent study by our working group revealed that the rs231775 single nucleotide polymorphism (SNP) in the CTLA-4 gene was associated with the survival of patients with sepsis and served as an independent prognostic variable. To further investigate the impact of CTLA-4 genetic variants on sepsis survival, we examined the effect of two functional SNPs, CTLA-4 rs733618 and CTLA-4 rs3087243, and inferred haplotypes, on the survival of 644 prospectively enrolled septic patients. Kaplan⁻Meier survival analysis revealed significantly lower 90-day mortality for rs3087243 G allele carriers (n = 502) than for AA-homozygous (n = 142) patients (27.3% vs. 40.8%, p = 0.0024). Likewise, lower 90-day mortality was observed for TAA haplotype-negative patients (n = 197; compound rs733618 T/rs231775 A/rs3087243 A) than for patients carrying the TAA haplotype (n = 447; 24.4% vs. 32.9%, p = 0.0265). Carrying the rs3087243 G allele hazard ratio (HR): 0.667; 95% confidence interval (CI): 0.489⁻0.909; p = 0.0103) or not carrying the TAA haplotype (HR: 0.685; 95% CI: 0.491⁻0.956; p = 0.0262) remained significant covariates for 90-day survival in the multivariate Cox regression analysis and thus served as independent prognostic variables. In conclusion, our findings underscore the significance of CTLA-4 genetic variants as predictors of survival of patients with sepsis."],["dc.description.sponsorship","Volkswagen Foundation"],["dc.identifier.doi","10.3390/jcm8010070"],["dc.identifier.eissn","2077-0383"],["dc.identifier.pmid","30634576"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15817"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59664"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","MDPI"],["dc.relation.eissn","2077-0383"],["dc.relation.issn","2077-0383"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject.ddc","610"],["dc.title","CTLA-4 Genetic Variants Predict Survival in Patients with Sepsis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["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.firstpage","2007"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","International Journal of Molecular Sciences"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Dücker, Christof"],["dc.date.accessioned","2022-04-01T10:03:18Z"],["dc.date.available","2022-04-01T10:03:18Z"],["dc.date.issued","2022"],["dc.date.updated","2022-09-03T12:11:42Z"],["dc.description.abstract","The organic cation transporter 1 (OCT1, SLC22A1) transports a large number of structurally diverse endogenous and exogenous substrates. There are numerous known competitive and non-competitive inhibitors of OCT1, but there are no studies systematically analyzing the relationship between transport, stimulation, and inhibition. Here, we tested in vitro OCT1 inhibition by OCT1 substrates and transport of OCT1 inhibitors under uniform analytical conditions. Beyond inhibition testing with two model substrates, we tested nine additional OCT1 substrates for their mutual inhibition. Inhibition of ASP+ uptake by most OCT1 substrates was weak. The model substrate sumatriptan, with its moderately stronger inhibitability, was used to confirm this. Interestingly, OCT1 substrates exhibiting stronger OCT1 inhibition were mainly biaromatic β-agonistic drugs, such as dobutamine, fenoterol, ractopamine and ritodrine. Biaromatic organic cations were both, strong inhibitors and good substrates, but many OCT1 substrates showed little pairwise inhibition. Surprisingly, sumatriptan did significantly enhance dobutamine uptake. This effect was concentration dependent and additional experiments indicated that efflux inhibition may be one of the underlying mechanisms. Our data suggests, that OCT1 substrates are mainly weak OCT1 inhibitors and among those inhibiting well, noncompetitive inhibition could be responsible. Weak competitive inhibition confirms that OCT1 inhibition screenings poorly predict OCT1 substrates. Additionally, we showed that the OCT1 substrate sumatriptan can enhance uptake of some other OCT1 substrates. OCT1 transport stimulation was already observed earlier but is still poorly understood. Low OCT1 uptake inhibition and strong OCT1 efflux inhibition could be mechanisms exploitable for enhancing transport."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.3390/ijms23042007"],["dc.identifier.pii","ijms23042007"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/106137"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-530"],["dc.relation.eissn","1422-0067"],["dc.rights","CC BY 4.0"],["dc.title","Relationships between Inhibition, Transport and Enhanced Transport via the Organic Cation Transporter 1"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Ansari, Salim"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Müller, Simon F."],["dc.contributor.author","Lowjaga, Kira A. A. T."],["dc.contributor.author","Geyer, Joachim"],["dc.contributor.author","Tzvetkov, Mladen V."],["dc.contributor.author","Brockmöller, Jürgen"],["dc.date.accessioned","2021-04-14T08:24:24Z"],["dc.date.available","2021-04-14T08:24:24Z"],["dc.date.issued","2020"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.1038/s41598-020-71051-5"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17822"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81279"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.notes.intern","Merged from goescholar"],["dc.relation.eissn","2045-2322"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","A double-Flp-in method for stable overexpression of two genes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","S0006295221003671"],["dc.bibliographiccitation.firstpage","114751"],["dc.bibliographiccitation.journal","Biochemical Pharmacology"],["dc.contributor.author","Sachkova, Alexandra"],["dc.contributor.author","Doetsch, David Alexander"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Ansari, Salim"],["dc.date.accessioned","2021-09-01T06:42:42Z"],["dc.date.available","2021-09-01T06:42:42Z"],["dc.date.issued","2021"],["dc.identifier.doi","10.1016/j.bcp.2021.114751"],["dc.identifier.pii","S0006295221003671"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/89122"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-455"],["dc.relation.issn","0006-2952"],["dc.title","How do psychostimulants enter the human brain? Analysis of the role of the proton-organic cation antiporter"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","12403"],["dc.bibliographiccitation.issue","18"],["dc.bibliographiccitation.journal","Journal of Medicinal Chemistry"],["dc.bibliographiccitation.lastpage","12416"],["dc.bibliographiccitation.volume","65"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Dücker, Christof"],["dc.date.accessioned","2022-10-04T10:21:11Z"],["dc.date.available","2022-10-04T10:21:11Z"],["dc.date.issued","2022"],["dc.identifier.doi","10.1021/acs.jmedchem.2c01075"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/114345"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-600"],["dc.relation.eissn","1520-4804"],["dc.relation.issn","0022-2623"],["dc.title","Substrates and Inhibitors of the Organic Cation Transporter 3 and Comparison with OCT1 and OCT2"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1664"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Biomolecules"],["dc.bibliographiccitation.volume","12"],["dc.contributor.affiliation","Redeker, Kyra-Elisa Maria; 1Institute of Clinical Pharmacology, University Medical Centre Göttingen, 37075 Göttingen, Germany"],["dc.contributor.affiliation","Jensen, Ole; 1Institute of Clinical Pharmacology, University Medical Centre Göttingen, 37075 Göttingen, Germany"],["dc.contributor.affiliation","Gebauer, Lukas; 1Institute of Clinical Pharmacology, University Medical Centre Göttingen, 37075 Göttingen, Germany"],["dc.contributor.affiliation","Meyer-Tönnies, Marleen Julia; 2Department of General Pharmacology, Institute of Pharmacology, Centre of Drug Absorption and Transport (C-DAT), University Medical Centre Greifswald, 17487 Greifswald, Germany"],["dc.contributor.affiliation","Brockmöller, Jürgen; 1Institute of Clinical Pharmacology, University Medical Centre Göttingen, 37075 Göttingen, Germany"],["dc.contributor.author","Redeker, Kyra-Elisa Maria"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Meyer-Tönnies, Marleen Julia"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.date.accessioned","2022-12-07T15:46:09Z"],["dc.date.available","2022-12-07T15:46:09Z"],["dc.date.issued","2022-11-09"],["dc.date.updated","2022-12-07T10:16:16Z"],["dc.description.abstract","The human organic cation transporter 1 (OCT1) is expressed in the liver and mediates hepatocellular uptake of organic cations. However, some studies have indicated that OCT1 could transport neutral or even anionic substrates. This capability is interesting concerning protein-substrate interactions and the clinical relevance of OCT1. To better understand the transport of neutral, anionic, or zwitterionic substrates, we used HEK293 cells overexpressing wild-type OCT1 and a variant in which we changed the putative substrate binding site (aspartate474) to a neutral amino acid. The uncharged drugs trimethoprim, lamivudine, and emtricitabine were good substrates of hOCT1. However, the uncharged drugs zalcitabine and lamotrigine, and the anionic levofloxacin, and prostaglandins E2 and F2α, were transported with lower activity. Finally, we could detect only extremely weak transport rates of acyclovir, ganciclovir, and stachydrine. Deleting aspartate474 had a similar transport-lowering effect on anionic substrates as on cationic substrates, indicating that aspartate474 might be relevant for intra-protein, rather than substrate-protein, interactions. Cellular uptake of the atypical substrates by the naturally occurring frequent variants OCT1*2 (methionine420del) and OCT1*3 (arginine61cysteine) was similarly reduced, as it is known for typical organic cations. Thus, to comprehensively understand the substrate spectrum and transport mechanisms of OCT1, one should also look at organic anions."],["dc.description.sponsorship","German Research Foundation (DFG, Deutsche Forschungsgemeinschaft)"],["dc.identifier.doi","10.3390/biom12111664"],["dc.identifier.pii","biom12111664"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/118466"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.relation.eissn","2218-273X"],["dc.rights","CC BY 4.0"],["dc.title","Atypical Substrates of the Organic Cation Transporter 1"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","S0006295221004974"],["dc.bibliographiccitation.firstpage","114871"],["dc.bibliographiccitation.journal","Biochemical Pharmacology"],["dc.bibliographiccitation.volume","197"],["dc.contributor.author","Gebauer, Lukas"],["dc.contributor.author","Arul Murugan, N."],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Rafehi, Muhammad"],["dc.date.accessioned","2022-01-11T14:07:49Z"],["dc.date.available","2022-01-11T14:07:49Z"],["dc.date.issued","2022"],["dc.identifier.doi","10.1016/j.bcp.2021.114871"],["dc.identifier.pii","S0006295221004974"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/97873"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-507"],["dc.relation.issn","0006-2952"],["dc.title","Molecular basis for stereoselective transport of fenoterol by the organic cation transporters 1 and 2"],["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","113731"],["dc.bibliographiccitation.journal","Biochemical Pharmacology"],["dc.bibliographiccitation.volume","171"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.date.accessioned","2020-10-22T08:56:04Z"],["dc.date.available","2020-10-22T08:56:04Z"],["dc.date.issued","2020"],["dc.description.abstract","Stereoselectivity is well described for receptor binding and enzyme catalysis, but so far has only been scarcely investigated in carrier-mediated membrane transport. We thus studied transport kinetics of racemic (anti)adrenergic drugs by the organic cation transporters OCT1 (wild-type and allelic variants), OCT2, OCT3, MATE1, and MATE2-K with a focus on stereospecificity. OCT1 showed stereoselective uptake with up to 2-fold higher vmax over their corresponding counterpart enantiomers for (R,R)-fenoterol, (R,R)-formoterol, (S)-salbutamol, (S)-acebutolol, and (S)-atenolol. Orciprenaline and etilefrine were also transported stereoselectively. The Km was 2.1-fold and 1.5-fold lower for the (S,S)-enantiomers of fenoterol and formoterol, while no significant difference in Km was seen for the other aforementioned drugs. Common OCT1 variants showed similar enantiopreference to wild-type OCT1, with a few notable exceptions (e.g. a switch in enantiospecificity for fenoterol in OCT1 2 compared to the wild-type). Other cation transporters showed strong differences to OCT1 in stereoselectivity and transport activity: The closely related OCT2 displayed a 20-fold higher vmax for (S,S)-fenoterol compared to (R,R)-fenoterol and OCT2 and OCT3 showed 3.5-fold and 4.6-fold higher vmax for the pharmacologically active (R)-salbutamol over (S)-salbutamol. MATE1 and MATE2-K generally mediated transport with a higher capacity but lower affinity compared to OCT1, with moderate stereoselectivity. Our kinetic studies showed that significant stereoselectivity exists in solute carrier-mediated membrane transport of racemic beta-adrenergic drugs with surprising, and in some instances even opposing, preferences between closely related organic cation transporters. This may be relevant for drug therapy, given the strong involvement of these transporters in hepatic and renal drug elimination."],["dc.identifier.doi","10.1016/j.bcp.2019.113731"],["dc.identifier.pmid","31783011"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68028"],["dc.language.iso","en"],["dc.relation.eissn","1873-2968"],["dc.relation.issn","0006-2952"],["dc.relation.orgunit","Institut für Klinische Pharmakologie"],["dc.title","Stereoselective cell uptake of adrenergic agonists and antagonists by organic cation transporters"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]