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 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","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.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.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","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"]]