Jensen, Ole

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

[["dc.bibliographiccitation.firstpage","1297"],["dc.bibliographiccitation.journal","Frontiers in Pharmacology"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Faltraco, Frank"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Prukop, Thomas"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Grytzmann, Aileen"],["dc.contributor.author","Berger, Ralf Günter"],["dc.contributor.author","Krings, Ulrich"],["dc.contributor.author","Vormfelde, Stefan Viktor"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Blome, Felix G."],["dc.date.accessioned","2020-10-22T08:52:50Z"],["dc.date.available","2020-10-22T08:52:50Z"],["dc.date.issued","2019"],["dc.description.abstract","Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. In vitro data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype. Since tyramine is a prototypic substrate of monoamine oxidase A (MAO-A), genetic polymorphisms in MAO-A may also be relevant. The aims of this study were to identify to what extent the interindividual variation in pharmacokinetics and pharmacodynamics of tyramine is determined by genetic polymorphisms in OCT1, CYP2D6, and MAO-A. Beyond that, we wanted to evaluate tyramine as probe drug for the in vivo activity of MAO-A and OCT1. Therefore, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tyramine were studied in 88 healthy volunteers after oral administration of a 400 mg dose. We observed a strong interindividual variation in systemic tyramine exposure, with a mean AUC of 3.74 min µg/ml and a high mean CL/F ratio of 107 l/min. On average, as much as 76.8% of the dose was recovered in urine in form of the MAO-catalysed metabolite 4-hydroxyphenylacetic acid (4-HPAA), confirming that oxidative deamination by MAO-A is the quantitatively most relevant metabolic pathway. Systemic exposure of 4-HPAA varied only up to 3-fold, indicating no strong heritable variation in peripheral MAO-A activity. Systolic blood pressure increased by more than 10 mmHg in 71% of the volunteers and correlated strongly with systemic tyramine concentration. In less than 10% of participants, individually variable blood pressure peaks by >40 mmHg above baseline were observed at tyramine concentrations of >60 µg/l. Unexpectedly, the functionally relevant polymorphisms in OCT1 and CYP2D6, including the CYP2D6 poor and ultra-rapid metaboliser genotypes, did not significantly affect tyramine pharmacokinetics or pharmacodynamics. Also, the MOA-A genotypes, which had been associated in several earlier studies with neuropsychiatric phenotypes, had no significant effects on tyramine pharmacokinetics or its metabolism to 4-HPAA. Thus, variation in tyramine pharmacokinetics and pharmacodynamics is not explained by obvious genomic variation, and human tyramine metabolism did not indicate the existence of ultra-low or -high MAO-A activity."],["dc.identifier.doi","10.3389/fphar.2019.01297"],["dc.identifier.pmid","31736764"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16579"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/68027"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1663-9812"],["dc.relation.issn","1663-9812"],["dc.relation.orgunit","Institut für Klinische Pharmakologie"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Highly Variable Pharmacokinetics of Tyramine in Humans and Polymorphisms in OCT1, CYP2D6, and MAO-A"],["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","Steimer, Werner"],["dc.contributor.author","Pischa, Konstanze"],["dc.contributor.author","Leucht, Stefan"],["dc.contributor.author","Kullmann, Maria"],["dc.contributor.author","Ouethy, Typhaine"],["dc.contributor.author","Rafehi, Muhammad"],["dc.contributor.author","Matthaei, Johannes"],["dc.contributor.author","Brockmöller, Jürgen"],["dc.contributor.author","Jensen, Ole"],["dc.contributor.author","Tzvetkov, Mladen Vassilev"],["dc.date.accessioned","2021-05-26T07:05:59Z"],["dc.date.available","2021-05-26T07:05:59Z"],["dc.date.issued","2021"],["dc.description.abstract","The tricyclic antidepressant amitriptyline is frequently prescribed but its use is limited by its narrow therapeutic range and large variation in pharmacokinetics. Apart from interindividual differences in the activity of the metabolising enzymes cytochrome P450 (CYP) 2D6 and 2C19, genetic polymorphism of the hepatic influx transporter organic cation transporter 1 (OCT1) could be contributing to interindividual variation in pharmacokinetics. Here, the impact of OCT1 genetic variation on the pharmacokinetics of amitriptyline and its active metabolite nortriptyline was studied in vitro as well as in healthy volunteers and in depressive disorder patients. Amitriptyline and nortriptyline were found to inhibit OCT1 in recombinant cells with IC50 values of 28.6 and 40.4 µM. Thirty other antidepressant and neuroleptic drugs were also found to be moderate to strong OCT1 inhibitors with IC50 values in the micromolar range. However, in 35 healthy volunteers, preselected for their OCT1 genotypes, who received a single dose of 25 mg amitriptyline, no significant effects on amitriptyline and nortriptyline pharmacokinetics could be attributed to OCT1 genetic polymorphism. In contrast, the strong impact of the CYP2D6 genotype on amitriptyline and nortriptyline pharmacokinetics and of the CYP2C19 genotype on nortriptyline was confirmed. In addition, acylcarnitine derivatives were measured as endogenous biomarkers for OCT1 activity. The mean plasma concentrations of isobutyrylcarnitine and 2-methylbutyrylcarnitine were higher in participants with two active OCT1 alleles compared to those with zero OCT1 activity, further supporting their role as endogenous in vivo biomarkers for OCT1 activity. A moderate reduction in plasma isobutyrylcarnitine concentrations occurred at the time points at which amitriptyline plasma concentrations were the highest. In a second, independent study sample of 50 patients who underwent amitriptyline therapy of 75 mg twice daily, a significant trend of increasing amitriptyline plasma concentrations with decreasing OCT1 activity was observed (p = 0.018), while nortriptyline plasma concentrations were unaffected by the OCT1 genotype. Altogether, this comprehensive study showed that OCT1 activity does not appear to be a major factor determining amitriptyline and nortriptyline pharmacokinetics and that hepatic uptake occurs mainly through other mechanisms."],["dc.identifier.doi","10.3389/fphar.2021.688950"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/84733"],["dc.language.iso","en"],["dc.notes.intern","DeepGreen Import"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1663-9812"],["dc.relation.issn","1663-9812"],["dc.rights","CC BY 4.0"],["dc.title","Effects of Genetic Polymorphism in CYP2D6, CYP2C19, and the Organic Cation Transporter OCT1 on Amitriptyline Pharmacokinetics in Healthy Volunteers and Depressive Disorder Patients"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]