Matthaei, Johannes

[["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","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"]]