116 results on '"Kerb R"'
Search Results
2. 10. First PIPAC in-human application
- Author
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Solass, W., primary, Kerb, R., additional, Mürdter, T., additional, Giger-Pabst, U., additional, Strumberg, D., additional, Tempfer, C., additional, Zieren, J., additional, Schwab, M., additional, and Reymond, M. A., additional
- Published
- 2014
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3. Variability in human hepatic MRP4 expression: influence of cholestasis and genotype
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Gradhand, U, Lang, T, Schaeffeler, E, Glaeser, H, Tegude, H, Klein, K, Fritz, P, Jedlitschky, G, Kroemer, H K, Bachmakov, I, Anwald, B, Kerb, R, Zanger, U M, Eichelbaum, M, Schwab, M, and Fromm, M F
- Published
- 2008
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4. The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels
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Kerb, R, Aynacioglu, A S, Brockmöller, J, Schlagenhaufer, R, Bauer, S, Szekeres, T, Hamwi, A, Fritzer-Szekeres, M, Baumgartner, C, Öngen, H Z, Güzelbey, P, Roots, I, and Brinkmann, U
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- 2001
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5. Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans
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Brockmoeller, J., Matthaei, J., Bonat, W. H., Jacob Hjelmborg, Kerb, R., and Schwab, M.
- Published
- 2019
6. Heritable Deficiency of Glutathione S-Transferases T1 and M1 and UV-Light Sensitivity of the Skin: PII-42
- Author
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Roots, I., Kerb, R., and Brockmöller, J.
- Published
- 1996
7. Heritability of Caffeine Metabolism: Environmental Effects Masking Genetic Effects on CYP1A2 Activity but Not on NAT2
- Author
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Matthaei, J, primary, Tzvetkov, MV, additional, Strube, J, additional, Sehrt, D, additional, Sachse‐Seeboth, C, additional, Hjelmborg, JB, additional, Möller, S, additional, Halekoh, U, additional, Hofmann, U, additional, Schwab, M, additional, Kerb, R, additional, and Brockmöller, J, additional
- Published
- 2016
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8. A twin study using unlabelled 12C and labeled 13C caffeine orally revealing common environmental effects on CYP1A2 activity but almost no heritability of CYP1A2 activity
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Matthaei, J, Schwab, M, Kerb, R, Hofmann, U, Sehrt, D, Sachse-Seeboth, C, Strube, J, Brockmöller, J, Matthaei, J, Schwab, M, Kerb, R, Hofmann, U, Sehrt, D, Sachse-Seeboth, C, Strube, J, and Brockmöller, J
- Published
- 2015
9. Systemische und lokale Verteilung von Doxorubicin nach Pressurized IntraPeritonal Aerosol Chemotherapie (PIPAC) im Menschen
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Pabst-Giger, U, Kerb, R, Mürdter, T, Zieren, J, Schwab, M, and Reymond, MA
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Einleitung: Die Wirksamkeit der intraperitonealen Chemotherapie ist limitiert, zum einen durch die schlechte Verteilung der Chemotherapeutika innerhalb des Abdomens und zum anderen durch die ungenügende Penetration in das Gewebe (Tumorknoten). Es wurde in verschiedenen Modellen gezeigt, dass die[for full text, please go to the a.m. URL], 130. Kongress der Deutschen Gesellschaft für Chirurgie
- Published
- 2013
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10. Clinical Translation in the Virtual Liver Network
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Kuepfer, L, primary, Kerb, R, additional, and Henney, AM, additional
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- 2014
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11. The predictive value of MDR1, CYP2C9, and CYP2C19 polymorphisms for phenytoin plasma levels
- Author
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Kerb, R., Aynacioglu, A.S., Brockmöller, J., Schlagenhaufer, R., Bauer, S., Szekeres, T., Hamwi, A., Fritzer-Szekeres, M., Baumgartner, C., Öngen, H.Z., Güzelbey, P., Roots, I., and Brinkmann, U.
- Subjects
Male ,analysis of variance ,Adolescent ,cytochrome P450 ,genotype ,anticonvulsive agent ,steroid monooxygenase ,prediction and forecasting ,Mixed Function Oxygenases ,TDM ,Cytochrome P-450 Enzyme System ,blood ,Predictive Value of Tests ,chi square distribution ,middle aged ,Humans ,genetic polymorphism ,genetics ,mixed function oxidase ,human ,Polymorphism ,steroid 16alpha monooxygenase ,gene ,drug monitoring ,Aged, 80 and over ,CYP2C9 protein, human ,Chi-Square Distribution ,Polymorphism, Genetic ,CYP2C19 protein, human ,adult ,phenytoin ,article ,unspecific monooxygenase ,aged ,female ,Steroid 16-alpha-Hydroxylase ,statistics ,Steroid Hydroxylases ,Pharmacogenetlcs ,Anticonvulsants ,Aryl Hydrocarbon Hydroxylases ,Genes, MDR - Abstract
Phenytoin, an anticonvulsant, exhibits nonlinear pharmacokinetics with large interindividual differences. Because of its small therapeutic range with the risk of therapeutic failure or adverse drug effects in susceptible persons, therapeutic drug monitoring is frequently applied. The interindividual differences in dose response can partially be explained by known genetic polymorphisms in the metabolic enzyme CYP2C9 but a large deal of individual variability remains still unexplained. Part of this variability might be accounted for by variable uptake of phenytoin, which is a substrate of p-glycoprotein, encoded by the human MDR1 gene. We evaluated, whether phenytoin plasma levels correlate with a polymorphism in the MDR1 gene, C3435T, which is associated with intestinal PCP activity. Genotyping and analyses of plasma levels of phenytoin and metabolites in 96 healthy Turkish volunteers showed that the MDR1C > T3435 polymorphism affects phenytoin plasma levels (P = 0.064) and the metabolic ratio of p-HPPH vs phenytoin (MDR1*TT genotype, P = 0.026). The MDR1*CC genotype is more common in volunteers with low phenytoin levels (P ≤ 0.001, χ2 test). A combined analysis of variable alleles of CYP2C9, 2C19 and MDR1 revealed that the number of mutant CYP2C9 alleles is a major determinant, the number of MDR1*T alleles further contributes to the prediction of phenytoin plasma levels and CYP2C19*2 does not explain individual variability. The regression equation that fitted the data best included the number of mutant CYP2C9 and MDR*T alleles as predictory variables and explained 15.4% of the variability of phenytoin data (r2 = 0.154, P = 0.0002). Furthermore, analysis of CYP2C9 and MDR1 genotypes in 35 phenytoin-treated patients recruited from therapeutic drug monitoring showed that combined CYP2C9 and MDR1 analysis has some predictive value not only in the controlled settings of a clinical trial, but also in the daily clinical practice. © 2001 Nature Publishing Group All rights reserved.
- Published
- 2001
12. NIPAC (Normotherme IntraPeritoneale Aerosol Chemotherapie) kann eine Tumorregression bei Peritonealkarzinose im Menschen induzieren
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Solaß, W, primary, Kerb, R, additional, Borgstedt, R, additional, Förster, C, additional, Mürdter, T, additional, Weissinger, F, additional, Tannapfel, A, additional, Zieren, J, additional, Schwab, M, additional, and Reymond, MA, additional
- Published
- 2012
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13. W34 FVIIA PLASMA LEVELS: INFLUENCE OF F7, F10 AND EPCR (ENDOTHELIAL PROTEIN C RECEPTOR) SNPS
- Author
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Kalies, I., primary, Knutsson, M., additional, Siegbahn, A., additional, Syvänen, A.-C., additional, Lind, L., additional, and Kerb, R., additional
- Published
- 2010
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14. Variability in human hepatic MRP4 expression: influence of cholestasis and genotype
- Author
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Gradhand, U, primary, Lang, T, additional, Schaeffeler, E, additional, Glaeser, H, additional, Tegude, H, additional, Klein, K, additional, Fritz, P, additional, Jedlitschky, G, additional, Kroemer, H K, additional, Bachmakov, I, additional, Anwald, B, additional, Kerb, R, additional, Zanger, U M, additional, Eichelbaum, M, additional, Schwab, M, additional, and Fromm, M F, additional
- Published
- 2007
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15. Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists
- Author
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BABAOGLU, M, primary, BAYAR, B, additional, AYNACIOGLU, A, additional, KERB, R, additional, ABALI, H, additional, CELIK, I, additional, and BOZKURT, A, additional
- Published
- 2005
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16. Effect of grapefruit juice on digoxin pharmacokinetics in humans
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BECQUEMONT, L, primary, VERSTUYFT, C, additional, KERB, R, additional, BRINKMANN, U, additional, LEBOT, M, additional, JAILLON, P, additional, and FUNCKBRENTANO, C, additional
- Published
- 2001
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17. Polymorphisms in xenobiotic conjugation and disease predisposition
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Brockmöller, J., primary, Cascorbi, L., additional, Kerb, R., additional, and Roots, L., additional
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- 1998
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18. Hypericin and Pseudohypericin: Pharmacokinetics and Effects on Photosensitivity in Humans
- Author
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Brockmöller, J., primary, Reum, T., additional, Bauer, S., additional, Kerb, R., additional, Hübner, W.-D., additional, and Roots, I., additional
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- 1997
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19. Single-dose and steady-state pharmacokinetics of hypericin and pseudohypericin
- Author
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Kerb, R, primary, Brockmöller, J, additional, Staffeldt, B, additional, Ploch, M, additional, and Roots, I, additional
- Published
- 1996
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20. Pharmacokinetics of Hypericin and Pseudohypericin after Oral Intake of the Hypericum Perforatum Extract LI 160 in Healthy Volunteers
- Author
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Staffeldt, B., primary, Kerb, R., additional, Brockmöller, J., additional, Ploch, M., additional, and Roots, I., additional
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- 1994
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21. Correlation between trans-stilbene oxide-glutathione conjugation activity and the deletion mutation in the glutathione S-transferase class Mu gene detected by polymerase chain reaction
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Brockmöller, J., primary, Gross, D., additional, Kerb, R., additional, Drakoulis, N., additional, and Roots, I., additional
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- 1992
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22. Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group.
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Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M, and German 5-FU Toxicity Study Group
- Published
- 2008
23. Association of multidrug resistance in epilepsy with a polymorphism in the drug-transporter gene ABCB1.
- Author
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Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, and Sisodiya SM
- Published
- 2003
24. Hypericin and Pseudohypericin: Pharmacokinetics and Effects on Photosensitivity in Humans.
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Brockm�ller, J., Reum, T., Bauer, S., Kerb, R., H�bner, W.-D., and Roots, I.
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- 1997
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25. Concordance between Enzyme Activity and Genotype of Glutathione S-Transferase Theta (GSTT1)
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Bruhn, C., Brockmoeller, J., Kerb, R., Roots, I., and Borchert, H.-H.
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- 1998
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26. Polymorphisms in xenobiotic conjugation and disease predisposition
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Brockmoeller, J., Cascorbi, I., Kerb, R., Sachse, C., and Roots, I.
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- 1998
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27. BSEP and MDR3 sequence diversity and haplotype structure in primary sclerosing cholangitis, primary biliary cirrhosis and intrahepatic cholestasis of pregnancy.
- Author
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Pauli-Magnus, C., Kerb, R., Zodan-Marin, T., Lang, T., Fattinger, K., Kullak-Ublick, G. A., Beuers, U., and Meier, P. J.
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- 2004
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28. S7/L3 - Polymorphisms in xenobiotic conjugation and disease predisposition
- Author
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Brockmöller, J., Cascorbi, L., Kerb, R., and Roots, L.
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- 1998
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29. Prediction of Drug-Drug-Gene Interaction Scenarios of ( E )-Clomiphene and Its Metabolites Using Physiologically Based Pharmacokinetic Modeling.
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Kovar C, Kovar L, Rüdesheim S, Selzer D, Ganchev B, Kröner P, Igel S, Kerb R, Schaeffeler E, Mürdter TE, Schwab M, and Lehr T
- Abstract
Clomiphene, a selective estrogen receptor modulator (SERM), has been used for the treatment of anovulation for more than 50 years. However, since ( E )-clomiphene (( E )-Clom) and its metabolites are eliminated primarily via Cytochrome P450 (CYP) 2D6 and CYP3A4, exposure can be affected by CYP2D6 polymorphisms and concomitant use with CYP inhibitors. Thus, clomiphene therapy may be susceptible to drug-gene interactions (DGIs), drug-drug interactions (DDIs) and drug-drug-gene interactions (DDGIs). Physiologically based pharmacokinetic (PBPK) modeling is a tool to quantify such DGI and DD(G)I scenarios. This study aimed to develop a whole-body PBPK model of ( E )-Clom including three important metabolites to describe and predict DGI and DD(G)I effects. Model performance was evaluated both graphically and by calculating quantitative measures. Here, 90% of predicted C
max and 80% of AUClast values were within two-fold of the corresponding observed value for DGIs and DD(G)Is with clarithromycin and paroxetine. The model also revealed quantitative contributions of different CYP enzymes to the involved metabolic pathways of ( E )-Clom and its metabolites. The developed PBPK model can be employed to assess the exposure of ( E )-Clom and its active metabolites in as-yet unexplored DD(G)I scenarios in future studies.- Published
- 2022
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30. Physiologically Based Pharmacokinetic Modeling to Describe the CYP2D6 Activity Score-Dependent Metabolism of Paroxetine, Atomoxetine and Risperidone.
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Rüdesheim S, Selzer D, Mürdter T, Igel S, Kerb R, Schwab M, and Lehr T
- Abstract
The cytochrome P450 2D6 ( CYP2D6 ) genotype is the single most important determinant of CYP2D6 activity as well as interindividual and interpopulation variability in CYP2D6 activity. Here, the CYP2D6 activity score provides an established tool to categorize the large number of CYP2D6 alleles by activity and facilitates the process of genotype-to-phenotype translation. Compared to the broad traditional phenotype categories, the CYP2D6 activity score additionally serves as a superior scale of CYP2D6 activity due to its finer graduation. Physiologically based pharmacokinetic (PBPK) models have been successfully used to describe and predict the activity score-dependent metabolism of CYP2D6 substrates. This study aimed to describe CYP2D6 drug-gene interactions (DGIs) of important CYP2D6 substrates paroxetine, atomoxetine and risperidone by developing a substrate-independent approach to model their activity score-dependent metabolism. The models were developed in PK-Sim
® , using a total of 57 plasma concentration-time profiles, and showed good performance, especially in DGI scenarios where 10/12, 5/5 and 7/7 of DGI AUClast ratios and 9/12, 5/5 and 7/7 of DGI Cmax ratios were within the prediction success limits. Finally, the models were used to predict their compound's exposure for different CYP2D6 activity scores during steady state. Here, predicted DGI AUCss ratios were 3.4, 13.6 and 2.0 (poor metabolizers; activity score = 0) and 0.2, 0.5 and 0.95 (ultrarapid metabolizers; activity score = 3) for paroxetine, atomoxetine and risperidone active moiety (risperidone + 9-hydroxyrisperidone), respectively.- Published
- 2022
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31. Data-driven personalization of a physiologically based pharmacokinetic model for caffeine: A systematic assessment.
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Fendt R, Hofmann U, Schneider ARP, Schaeffeler E, Burghaus R, Yilmaz A, Blank LM, Kerb R, Lippert J, Schlender JF, Schwab M, and Kuepfer L
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- Adolescent, Adult, Caffeine administration & dosage, Computer Simulation, Dose-Response Relationship, Drug, Female, Glomerular Filtration Rate, Humans, Liver blood supply, Liver diagnostic imaging, Magnetic Resonance Imaging, Male, Middle Aged, Phenotype, Precision Medicine, Young Adult, Caffeine pharmacokinetics, Cytochrome P-450 CYP1A2 metabolism, Models, Biological
- Abstract
Physiologically based pharmacokinetic (PBPK) models have been proposed as a tool for more accurate individual pharmacokinetic (PK) predictions and model-informed precision dosing, but their application in clinical practice is still rare. This study systematically assesses the benefit of using individual patient information to improve PK predictions. A PBPK model of caffeine was stepwise personalized by using individual data on (1) demography, (2) physiology, and (3) cytochrome P450 (CYP) 1A2 phenotype of 48 healthy volunteers participating in a single-dose clinical study. Model performance was benchmarked against a caffeine base model simulated with parameters of an average individual. In the first step, virtual twins were generated based on the study subjects' demography (height, weight, age, sex), which implicated the rescaling of average organ volumes and blood flows. The accuracy of PK simulations improved compared with the base model. The percentage of predictions within 0.8-fold to 1.25-fold of the observed values increased from 45.8% (base model) to 57.8% (Step 1). However, setting physiological parameters (liver blood flow determined by magnetic resonance imaging, glomerular filtration rate, hematocrit) to measured values in the second step did not further improve the simulation result (59.1% in the 1.25-fold range). In the third step, virtual twins matching individual demography, physiology, and CYP1A2 activity considerably improved the simulation results. The percentage of data within the 1.25-fold range was 66.15%. This case study shows that individual PK profiles can be predicted more accurately by considering individual attributes and that personalized PBPK models could be a valuable tool for model-informed precision dosing approaches in the future., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2021
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32. Stereoselective quantification of phase 1 and 2 metabolites of clomiphene in human plasma and urine.
- Author
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Kröner P, Heinkele G, Kerb R, Igel S, Schwab M, and Mürdter TE
- Subjects
- Biotransformation, Chromatography, High Pressure Liquid, Chromatography, Liquid, Female, Humans, Reference Standards, Reproducibility of Results, Clomiphene, Tandem Mass Spectrometry
- Abstract
Clomiphene citrate is first line therapy of female infertility but is also frequently abused by athletes. Human biotransformation of clomiphene results in numerous phase 1 and phase 2 metabolites. The involvement of the polymorphic cytochrome P450 2D6 leads to a high inter-individual variability. To comprehensively investigate clomiphene metabolism in vivo we established a highly sensitive and specific UPLC-MS/MS method for the stereoselective quantification of clomiphene and its phase 1 and phase 2 metabolites in plasma and urine. Reference compounds and stable isotope labelled internal standards were synthesized in-house. High-throughput sample preparation was done by protein precipitation. Analytes were separated by UPLC on a C18 column (1.8 μm, 2.1 * 100 mm) using a gradient of 0.1% formic acid in acetonitrile in 0.1% aqueous formic acid and detected by positive ESI-MS/MS in MRM mode. The lower limit of quantification was below 1 nM for all analytes. The method was validated according to recent guidelines. However, due to absorption effects during sampling the quantification of metabolites in urine was limited to phase 2 metabolites. The method was successfully applied to determine the pharmacokinetic of (E)- and (Z)-clomiphene and 14 metabolites following a single dose of 100 mg clomiphene citrate in 3 healthy subjects and proofed to be an essential tool to comprehensively investigate the human biotransformation of clomiphene., (Copyright © 2020 Elsevier B.V. All rights reserved.)
- Published
- 2021
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33. Inherited and Acquired Determinants of Hepatic CYP3A Activity in Humans.
- Author
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Matthaei J, Bonat WH, Kerb R, Tzvetkov MV, Strube J, Brunke S, Sachse-Seeboth C, Sehrt D, Hofmann U, von Bornemann Hjelmborg J, Schwab M, and Brockmöller J
- 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., (Copyright © 2020 Matthaei, Bonat, Kerb, Tzvetkov, Strube, Brunke, Sachse-Seeboth, Sehrt, Hofmann, von Bornemann Hjelmborg, Schwab and Brockmöller.)- Published
- 2020
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34. Population Pharmacokinetics of Mefloquine Intermittent Preventive Treatment for Malaria in Pregnancy in Gabon.
- Author
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Ramharter M, Schwab M, Mombo-Ngoma G, Zoleko Manego R, Akerey-Diop D, Basra A, Mackanga JR, Würbel H, Wojtyniak JG, Gonzalez R, Hofmann U, Geditz M, Matsiegui PB, Kremsner PG, Menendez C, Kerb R, and Lehr T
- Subjects
- Adolescent, Adult, Antimalarials pharmacokinetics, Drug Combinations, Female, Humans, Mefloquine pharmacokinetics, Pharmacokinetics, Plasmodium falciparum drug effects, Plasmodium falciparum metabolism, Pregnancy, Pyrimethamine pharmacokinetics, Pyrimethamine therapeutic use, Sulfadoxine pharmacokinetics, Sulfadoxine therapeutic use, Young Adult, Antimalarials therapeutic use, Malaria drug therapy, Mefloquine analogs & derivatives, Mefloquine therapeutic use
- Abstract
Mefloquine was evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first-line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and the metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated, and potential covariates influencing the pharmacokinetic properties were assessed. A population pharmacokinetic analysis was performed with 264 pregnant women from a randomized controlled trial evaluating a single and a split-dose regimen of two 15-mg/kg mefloquine doses at least 1 month apart versus SP-IPTp. Both enantiomers of mefloquine and its carboxy-metabolite (CMQ), measured in plasma and cord samples, were applied for pharmacokinetic modelling using NONMEM 7.3. Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group, mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated ( r
2 = 0.84) at delivery. With the dosing regimens investigated, prophylactic levels are not constantly achieved. A modeling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented. This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens; however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as a valuable tool for researchers and clinicians to develop and optimize alternative dosing regimens for IPTp in pregnant women., (Copyright © 2019 American Society for Microbiology.)- Published
- 2019
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35. Translational learning from clinical studies predicts drug pharmacokinetics across patient populations.
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Krauss M, Hofmann U, Schafmayer C, Igel S, Schlender J, Mueller C, Brosch M, von Schoenfels W, Erhart W, Schuppert A, Block M, Schaeffeler E, Boehmer G, Goerlitz L, Hoecker J, Lippert J, Kerb R, Hampe J, Kuepfer L, and Schwab M
- Abstract
Early indication of late-stage failure of novel candidate drugs could be facilitated by continuous integration, assessment, and transfer of knowledge acquired along pharmaceutical development programs. We here present a translational systems pharmacology workflow that combines drug cocktail probing in a specifically designed clinical study, physiologically based pharmacokinetic modeling, and Bayesian statistics to identify and transfer (patho-)physiological and drug-specific knowledge across distinct patient populations. Our work builds on two clinical investigations, one with 103 healthy volunteers and one with 79 diseased patients from which we systematically derived physiological information from pharmacokinetic data for a reference probe drug (midazolam) at the single-patient level. Taking into account the acquired knowledge describing (patho-)physiological alterations in the patient cohort allowed the successful prediction of the population pharmacokinetics of a second, candidate probe drug (torsemide) in the patient population. In addition, we identified significant relations of the acquired physiological processes to patient metadata from liver biopsies. The presented prototypical systems pharmacology approach is a proof of concept for model-based translation across different stages of pharmaceutical development programs. Applied consistently, it has the potential to systematically improve predictivity of pharmacokinetic simulations by incorporating the results of clinical trials and translating them to subsequent studies.
- Published
- 2017
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36. 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.
- Author
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Matthaei J, Tzvetkov MV, Gal V, Sachse-Seeboth C, Sehrt D, Hjelmborg JB, Hofmann U, Schwab M, Kerb R, and Brockmöller J
- Subjects
- ATP Binding Cassette Transporter, Subfamily B genetics, Body Mass Index, Female, Gene-Environment Interaction, Genotype, Humans, Male, Membrane Transport Proteins, Multidrug Resistance-Associated Protein 2, Pharmacogenetics, Sex Factors, Twin Studies as Topic, Multidrug Resistance-Associated Proteins genetics, Propanolamines pharmacokinetics, Twins, Dizygotic genetics, Twins, Monozygotic genetics
- 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., Trial Registration: European clinical trials database number: EUDRA-CT 2008-006223-31. Registered 26 September 2008. ClinicalTrials.gov number: NCT01845194 .
- Published
- 2016
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37. Intramuscular Artesunate for Severe Malaria in African Children: A Multicenter Randomized Controlled Trial.
- Author
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Kremsner PG, Adegnika AA, Hounkpatin AB, Zinsou JF, Taylor TE, Chimalizeni Y, Liomba A, Kombila M, Bouyou-Akotet MK, Mawili Mboumba DP, Agbenyega T, Ansong D, Sylverken J, Ogutu BR, Otieno GA, Wangwe A, Bojang KA, Okomo U, Sanya-Isijola F, Newton CR, Njuguna P, Kazungu M, Kerb R, Geditz M, Schwab M, Velavan TP, Nguetse C, Köhler C, Issifou S, Bolte S, Engleitner T, Mordmüller B, and Krishna S
- Subjects
- Africa epidemiology, Artesunate, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Infant, Injections, Intramuscular, Malaria, Falciparum diagnosis, Male, Antimalarials administration & dosage, Artemisinins administration & dosage, Malaria, Falciparum drug therapy, Malaria, Falciparum epidemiology, Severity of Illness Index
- Abstract
Background: Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%)., Methods and Findings: This randomized controlled trial included children (0.5-10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥ 99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan-Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7 g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥ 99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI -7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥ 99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI -12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner., Conclusions: A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children., Trial Registration: Pan African Clinical Trials Registry PACTR201102000277177.
- Published
- 2016
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- View/download PDF
38. A new [2H]-labelled α-trichloroimidate glucuronic ester for the synthesis of deuterated drug conjugates.
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Heinkele G, Geditz MC, Ganchev B, Kerb R, Hofmann U, and Mürdter TE
- Subjects
- Chemistry Techniques, Synthetic methods, Acetamides chemical synthesis, Chloroacetates chemical synthesis, Deuterium chemistry, Glucuronides chemical synthesis, Radiopharmaceuticals chemical synthesis
- Abstract
A new reaction pathway for the synthesis of a [(2)H]-labelled trichloroacetimidate precursor for the preparation of glucuronides is described. Therewith, stable isotope-labelled drug glucuronides become accessible on a preparative scale, which can further be used as internal standards for quantitative analysis., (Copyright © 2014 John Wiley & Sons, Ltd.)
- Published
- 2014
- Full Text
- View/download PDF
39. Simultaneous quantification of mefloquine (+)- and (-)-enantiomers and the carboxy metabolite in dried blood spots by liquid chromatography/tandem mass spectrometry.
- Author
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Geditz MC, Lindner W, Lämmerhofer M, Heinkele G, Kerb R, Ramharter M, Schwab M, and Hofmann U
- Subjects
- Acetonitriles chemistry, Calibration, Female, Humans, Methanol chemistry, Pregnancy, Reproducibility of Results, Sensitivity and Specificity, Stereoisomerism, Water chemistry, Chromatography, Liquid methods, Dried Blood Spot Testing methods, Mefloquine chemistry, Tandem Mass Spectrometry methods
- Abstract
Mefloquine (MQ), a racemic mixture of (+)-(11S,12R)- and (-)-(11R,12S)-MQ, has been used for treatment and prophylaxis of malaria for almost 30 years. MQ is metabolized by the cytochrome P450 3A subfamily to 4-carboxymefloquine (CMQ), which shows no antimalarial activity in vitro. Highly stereospecific pharmacokinetics of MQ have been reported, although with contradictory results. This might be due to incorrect assignment of the absolute configuration as shown only recently. Gastrointestinal as well as neuropsychiatric adverse events were described after prophylaxis and treatment with MQ. Data are indicating that the tolerability of the enantiomers may vary considerably. An involvement of the main metabolite CMQ in the development of neuropsychiatric adverse events has also been supposed. Due to these inconsistent results we established a novel liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of MQ enantiomers and the metabolite CMQ to investigate the attribution of efficacy and adverse effects to the single enantiomers as well as the main metabolite. Separation of the MQ enantiomers was achieved on a quinidine-based zwitterionic chiral stationary phase column, CHIRALPAK(®) ZWIX(-) (3.0×150mm, 3μm) in an isocratic run using a pre-mixed eluent consisting of methanol/acetonitrile/water (49:49:2 v/v) with 25mM formic acid and 12.5mM ammonium formate. We used stable isotope-labelled analogues as internal standards. The method was validated according to the FDA guidelines. With a linear calibration range from 5 to 2000nM for the MQ enantiomers and from 13 to 2600nM for CMQ respectively, the method was successfully applied to dried blood spot (DBS) samples from patients under prophylactic MQ treatment. The method was also applicable for plasma samples., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2014
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40. LC-MS/MS method for the simultaneous quantification of artesunate and its metabolites dihydroartemisinin and dihydroartemisinin glucuronide in human plasma.
- Author
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Geditz MC, Heinkele G, Ahmed A, Kremsner PG, Kerb R, Schwab M, and Hofmann U
- Subjects
- Antimalarials metabolism, Artemisinins metabolism, Artesunate, Humans, Antimalarials blood, Artemisinins blood, Chromatography, Liquid methods, Glucuronides blood, Tandem Mass Spectrometry methods
- Abstract
Artesunate (AS), a hemisuccinate derivative of artemisinin, is readily soluble in water and can easily be used in formulations for parenteral treatment of severe malaria. AS is rapidly hydrolyzed to the active metabolite dihydroartemisinin (DHA) and primarily eliminated by biliary excretion after glucuronidation. To investigate systematically the AS metabolism and pharmacokinetics, a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of AS and its metabolites DHA and DHA glucuronide (DHAG) in human plasma samples was developed. Compared to previous methods, our method includes for the first time the quantification of the glucuronide metabolite using a newly synthesized stable isotope-labeled analogue as internal standard. Sample preparation was performed with only 50 μL plasma by high-throughput solid-phase extraction in the 96-well plate format. Separation of the analytes was achieved on a Poroshell 120 EC-C18 column (50*2.1 mm, 2.7 μm, Agilent Technologies, Waldbronn, Germany). The method was validated according to FDA guidelines. Calibration curves were linear over the entire range from 1 to 2,500 nM (0.4-961.1 ng/mL), 165 to 16,500 nM (46.9-4,691.8 ng/mL), and 4 to 10,000 nM (1.8-4,604.7 ng/mL) for AS, DHA, and DHAG, respectively. Intra- and interbatch accuracy, determined as a deviation between nominal and measured values, ranged from -5.7 to 3.5% and from 2.7 to 5.8%, respectively. The assay variability ranged from 1.5 to 10.9% for intra- and interbatch approaches. All analytes showed extraction recoveries above 85%. The method was successfully applied to plasma samples from patients under AS treatment.
- Published
- 2014
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41. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy.
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Solass W, Kerb R, Mürdter T, Giger-Pabst U, Strumberg D, Tempfer C, Zieren J, Schwab M, and Reymond MA
- Subjects
- Adult, Aerosols, Aged, Appendiceal Neoplasms mortality, Appendiceal Neoplasms pathology, Female, Humans, Injections, Intraperitoneal, Male, Middle Aged, Neoplasm Staging, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology, Peritoneal Neoplasms mortality, Peritoneal Neoplasms secondary, Stomach Neoplasms mortality, Stomach Neoplasms pathology, Survival Rate, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Appendiceal Neoplasms drug therapy, Ovarian Neoplasms drug therapy, Peritoneal Neoplasms drug therapy, Pressure, Stomach Neoplasms drug therapy
- Abstract
Background: Peritoneal carcinomatosis (PC) is an unmet medical need. Despite recent improvements, systemic chemotherapy has limited efficacy. We report the first application of intraperitoneal chemotherapy as a pressurized aerosol in human patients., Methods: Three end-stage patients with advanced PC from gastric, appendiceal, and ovarian origin were treated as a compassionate therapy. All patients had received previous systemic chemotherapy. A pressurized aerosol of CO2 loaded with doxorubicin 1.5 mg/m(2) and cisplatin 7.5 mg/m(2) (pressurized intraperitoneal aerosol chemotherapy, PIPAC) was applied into the abdomen for 30 min at a pressure of 12 mmHg and a temperature of 37 °C., Results: No side-effects >2 CTCAE were observed, and the procedures were well tolerated. Early hospital discharge was possible (days 2-5). Nuclear presence of doxorubicin was documented throughout the peritoneum, reaching high local concentration (≤4.1 μmol/g) and plasma concentration was low (4.0-6.2 ng/ml). PIPAC created no significant adhesions, could be repeated, and was applied 6×, 4×, and 2×. Two patients showed a complete and one a partial histological remission. Mean survival after the first PIPAC was 288 days. One patient is alive after 567 days., Conclusions: PIPAC shows superior pharmacological properties with high local concentration and low systemic exposure. PIPAC can induce regression of PC in chemoresistant tumors, using 10% of a usual systemic dose.
- Published
- 2014
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42. Functional characterization of protein variants of the human multidrug transporter ABCC2 by a novel targeted expression system in fibrosarcoma cells.
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Arlanov R, Porter A, Strand D, Brough R, Karpova D, Kerb R, Wojnowski L, Schwab M, and Lang T
- Subjects
- Black or African American genetics, Asian genetics, Cell Line, Tumor, Chloramines metabolism, Fibrosarcoma metabolism, Gene Expression Regulation drug effects, Genetic Variation, HEK293 Cells, Haplotypes, Humans, Multidrug Resistance-Associated Protein 2, Mutation, Missense, Recombinant Proteins genetics, Recombinant Proteins metabolism, Tetracycline pharmacology, Multidrug Resistance-Associated Proteins genetics, Multidrug Resistance-Associated Proteins metabolism
- Abstract
The multidrug resistance-associated protein 2 (MRP2/ABCC2) is involved in the efflux of endogenous and xenobiotic substrates, including several anticancer and antiviral drugs. The functional consequences of ABCC2 protein variants remain inconsistent, which may be due to shortcomings of the in vitro assays used. To study systematically the functional consequences of nonsynonymous ABCC2 variants, we used a novel "Screen and Insert" (ScIn) technology to achieve stable and highly reproducible expression of 13 ABCC2 variants in HT1080 cells. Western blotting revealed lower (30-65%) ABCC2 expression for D333G, R1174H, and R1181L as compared with wild type (WT; 100%), whereas the linked variant V1188E/C1515Y resulted in higher expression (150%). R1174H caused mislocalization of ABCC2 to the cytoplasm with an endoplasmic reticulum-like distribution. Variants N1244K and R1174H decreased transport of glutathione-methylfluorescein (GS-MF) and glutathione-monochlorobimane (GS-MCB) by 80% and 50%, respectively, whereas R1181L and P1291L reduced only GS-MCB transport by 50% as compared with WT. Contrary to protein data, the double variant V1188E/C1515Y decreased specific transport activity for GS-MF and GS-MCB by 40%. The ScIn approach is a feasible and reliable method to functionally characterize systematically ABCC2 variants. D333G, R1174H, R1181L, N1244K, P1291L, and double variant V1188E/C1515Y have been identified as most promising for further clinical evaluation., (© 2012 Wiley Periodicals, Inc.)
- Published
- 2012
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43. Genetic polymorphism of cytochrome P450 2D6 determines oestrogen receptor activity of the major infertility drug clomiphene via its active metabolites.
- Author
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Mürdter TE, Kerb R, Turpeinen M, Schroth W, Ganchev B, Böhmer GM, Igel S, Schaeffeler E, Zanger U, Brauch H, and Schwab M
- Subjects
- Biotransformation, Clomiphene analogs & derivatives, Clomiphene chemistry, Cytochrome P-450 CYP2D6 metabolism, Female, Genotype, Humans, Microsomes, Liver metabolism, Molecular Structure, Receptors, Estrogen metabolism, Recombinant Proteins metabolism, Clomiphene metabolism, Clomiphene pharmacology, Cytochrome P-450 CYP2D6 genetics, Estrogen Antagonists metabolism, Estrogen Antagonists pharmacology, Polymorphism, Genetic, Receptors, Estrogen antagonists & inhibitors
- Abstract
Clomiphene citrate is the most used drug for the treatment of female infertility, a common condition in western societies and developing countries. Despite dose escalation, up to 30% of women do not respond. Since clomiphene shares structural similarities with tamoxifen, which is predominantly bioactivated by the polymorphic cytochrome P450 (CYP) 2D6, we systematically explored clomiphene metabolism and action in vitro and in vivo by pharmacogenetic, -kinetic and -dynamic investigations. Human liver microsomes were incubated with clomiphene citrate and nine metabolites were identified by mass spectrometry and tested at the oestrogen receptor for their antagonistic capacity. (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed strongest inhibition of the oestrogen receptor activity with 50% inhibitory concentrations of 2.5 and 1.4 nm, respectively. CYP2D6 has been identified as the major enzyme involved in their formation using recombinant CYP450 isozymes as confirmed by inhibition experiments with CYP monoclonal antibodies. We correlated the CYP2D6 genotype of 30 human liver donors with the microsomal formation rate of active metabolites and observed a strong gene-dose effect. A healthy female volunteer study confirmed our in vitro data that the CYP2D6 polymorphism substantially determines the formation of the active clomiphene metabolites. Comparison of the C(max) of (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed 8 and 12 times lower concentrations in subjects with non-functional CYP2D6 alleles. Our results highlight (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene as the active clomiphene metabolites, the formation of which strongly depends on the polymorphic CYP2D6 enzyme. Our data provide first evidence of a biological rationale for the variability in the response to clomiphene treatment.
- Published
- 2012
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44. Quantification of clomiphene metabolite isomers in human plasma by rapid-resolution liquid chromatography-electrospray ionization-tandem mass spectrometry.
- Author
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Ganchev B, Heinkele G, Kerb R, Schwab M, and Mürdter TE
- Subjects
- Chromatography, Liquid methods, Clomiphene metabolism, Female, Humans, Isomerism, Selective Estrogen Receptor Modulators, Spectrometry, Mass, Electrospray Ionization methods, Clomiphene blood, Tandem Mass Spectrometry methods
- Abstract
Since the 1960s, clomiphene citrate is used for ovulation induction. Since nonresponse to clomiphene therapy is still not well understood, interindividual variability of clomiphene metabolism has been considered to be a plausible explanation. Therefore, a comprehensive, rapid, sensitive, and specific analytical method for the quantification of (E)- and (Z)-isomers of clomiphene and their putative N-desethyl, N,N-didesethyl, 4-hydroxy, and 4-hydroxy-N-desethyl metabolites, and the N-oxides in human plasma has been newly developed, using HPLC-tandem mass spectrometry and stable isotope-labeled internal standards. All standards other than the parent drug were synthesized in our laboratory. Following protein precipitation analytes were separated on a ZORBAX Eclipse plus C18 1.8 μm column with a gradient of 0.1% formic acid in water and 0.1% formic acid in acetonitrile and detected on a triple quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction monitoring mode. Lower limit of quantification for metabolites ranged from 0.06 ng/mL for clomiphene-N-oxides to 0.3 ng/mL for (E)-N-desethylclomiphene. The assay was validated according to FDA guidelines. Plasma levels of clomiphene and its metabolites were measured in two women after single-dose treatment with clomiphene.
- Published
- 2011
- Full Text
- View/download PDF
45. Pharmacogenetics of antimalarial drugs: effect on metabolism and transport.
- Author
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Kerb R, Fux R, Mörike K, Kremsner PG, Gil JP, Gleiter CH, and Schwab M
- Subjects
- Asian People genetics, Black People genetics, Humans, Organic Anion Transporters genetics, Pharmacogenetics, White People genetics, Antimalarials pharmacokinetics, Cytochrome P-450 Enzyme System genetics, Polymorphism, Single Nucleotide
- Abstract
The prevention and management of malaria is primarily based on the use of drugs. Clinical trials have however revealed that between individuals there is large variability in the pharmacokinetic profiles of many antimalarial drugs. The resulting variations in concentrations of the drug within plasma might lead to either suboptimum effectiveness or drug toxicity in some patients. The evidence is increasing that polymorphically expressed drug-metabolising enzymes, predominantly various cytochrome P450 isozymes but also drug transporters, might contribute to the variability in drug response (incomplete cure, relapse, or resistance) or toxicity experienced with antimalarial drugs. For example, there is a clear association between concentrations of proguanil within plasma and certain genetic polymorphisms of CYP2C19, and genetically established levels of CYP2C8 might have important clinical implications in the toxicity of amodiaquine. Variation in the expression of drug-metabolising enzymes and transport proteins affects the pharmacology of antimalarial drugs. Exploration of pharmacogenetics might help to optimise the use of antimalarial drugs.
- Published
- 2009
- Full Text
- View/download PDF
46. Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver.
- Author
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Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R, Zanger UM, Keppler D, Schwab M, and Schaeffeler E
- Subjects
- Biological Transport physiology, Cholestasis pathology, Gene Frequency genetics, Glucose metabolism, Haplotypes genetics, Hepatocytes metabolism, Hepatocytes pathology, Humans, Hypoglycemic Agents pharmacokinetics, Liver pathology, Metformin pharmacokinetics, Multivariate Analysis, Polymorphism, Single Nucleotide genetics, RNA, Messenger metabolism, White People genetics, Cholestasis metabolism, Liver metabolism, Octamer Transcription Factor-1 genetics, Octamer Transcription Factor-1 metabolism, Organic Cation Transport Proteins genetics, Organic Cation Transport Proteins metabolism
- Abstract
Unlabelled: An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide single-nucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113- and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P < or = 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P = 0.03)., Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin.
- Published
- 2009
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47. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.
- Author
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Lang C, Meier Y, Stieger B, Beuers U, Lang T, Kerb R, Kullak-Ublick GA, Meier PJ, and Pauli-Magnus C
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 11, Adolescent, Adult, Aged, Aged, 80 and over, Amino Acid Sequence, Cholestasis genetics, Cholestasis pathology, Female, Genetic Predisposition to Disease, Humans, Liver Diseases genetics, Liver Diseases pathology, Male, Middle Aged, Molecular Sequence Data, Protein Structure, Secondary, Taurocholic Acid metabolism, White People, ATP Binding Cassette Transporter, Subfamily B genetics, ATP-Binding Cassette Transporters genetics, Chemical and Drug Induced Liver Injury, Cholestasis chemically induced, Mutation, Polymorphism, Genetic
- Abstract
Objectives: Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms., Methods: ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury. Ninety-five healthy Caucasians served as the control group. Reference and mutant BSEP were expressed in Sf9 cells and ATP-dependent transport of [H]-taurocholate was measured in a rapid filtration assay., Results: Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P<0.05). The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional., Conclusion: In summary, our data support a role of ABCB11 and ABCB4 mutations and polymorphisms in drug-induced cholestasis. Genotyping of selected patients with acquired cholestasis might help to identify individuals with a genetic predisposition.
- Published
- 2007
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48. Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).
- Author
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Lang T, Haberl M, Jung D, Drescher A, Schlagenhaufer R, Keil A, Mornhinweg E, Stieger B, Kullak-Ublick GA, and Kerb R
- Subjects
- 5' Flanking Region genetics, ATP Binding Cassette Transporter, Subfamily B chemistry, ATP Binding Cassette Transporter, Subfamily B metabolism, ATP Binding Cassette Transporter, Subfamily B, Member 11, ATP-Binding Cassette Transporters chemistry, ATP-Binding Cassette Transporters metabolism, Amino Acid Sequence, Bile Acids and Salts metabolism, Cell Line, Tumor, Cholestasis ethnology, Cholestasis genetics, Cholestasis metabolism, Gene Frequency, Genes, Reporter, Genetic Testing, Humans, Linkage Disequilibrium, Liver metabolism, Luciferases, Models, Genetic, Molecular Sequence Data, Promoter Regions, Genetic genetics, Sequence Analysis, DNA methods, Transfection, ATP Binding Cassette Transporter, Subfamily B genetics, ATP-Binding Cassette Transporters genetics, Black or African American genetics, Asian People genetics, Haplotypes, Polymorphism, Single Nucleotide, White People genetics
- Abstract
Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g., progressive familial intrahepatic cholestasis 2 (PFIC2), PFIC3, and intrahepatic cholestasis of pregnancy], and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy populations of different ethnic backgrounds. All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin. In total, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively; among them, 14 and 28 exonic polymorphisms, and 8 and 10 protein-altering variants, of which 4 were predicted to have functional consequences. Both genes showed substantial ethnic differences with respect to allele number, frequency of common and population-specific sites, and patterns of linkage disequilibrium. Population genetic analysis suggested some selective pressure against changes in the protein, supporting the important endogenous role of these transporters. Haplotype variability was greater in ABCB11 than in ABCB4. An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type. Our results contribute to a better understanding of the molecular basis and of ethnic differences in drug response, and provide a valuable tool for future research on the heredity of cholestatic liver injury.
- Published
- 2006
- Full Text
- View/download PDF
49. Neonatal jaundice and bilirubin UDP-glucuronosyl transferase 1A1 gene polymorphism in Turkish patients.
- Author
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Babaoglu MO, Yigit S, Aynacioglu AS, Kerb R, Yurdakok M, and Bozkurt A
- Subjects
- Case-Control Studies, Female, Genotype, Humans, Infant, Newborn, Male, Polymorphism, Genetic, Turkey epidemiology, Glucuronosyltransferase genetics, Jaundice, Neonatal genetics
- Abstract
Bilirubin uridine diphosphate-glucuronosyltransferase (B-UGT) is the rate-limiting enzyme for the conjugation of bilirubin with glucuronic acid in its excretion process into the bile. Variations in B-UGT gene (UGT-1A1) have been related to disorders characterised by hyperbilirubinaemia. The aim of this study was to investigate whether the number of thymine-adenine repeats in the promoter region of UGT-1A1 was related to non-physiologic hyperbilirubinemia of unexplained aetiology in Turkish newborns. These patients (n=106) were genotyped for their thymine-adenine repeat number in the promoter region of UGT-1A1, and were divided into two groups according to their bilirubin level. Forty-nine newborns with bilirubin levels higher than 17 mg/dl within the first ten days of life comprised the hyperbilirubinaemia group and 25 newborns with bilirubin levels higher than 10 mg/dl after fifteen days of life formed the prolonged jaundice group. Thirty-two newborns were included as healthy controls. The observed frequencies for the wild-type six repeat allele thymine-adenine (TA(6)) within each subject group were similar (P>0.05; 75.5%, 78.0% and 73.4%, respectively). Likewise, the distribution of TA(6/6), TA(6/7) and TA(7/7) genotypes among three groups were similar. These results imply that the TA(7) repeat allele of UGT1A1 (UGT1A1*28) is a common variant in the Turkish population. Our results do not suggest an association between thymine-adenine repeat polymorphism of UGT1A1 and hyperbilirubinaemia of unexplained aetiology or prolonged jaundice in Turkish neonates.
- Published
- 2006
- Full Text
- View/download PDF
50. Implications of genetic polymorphisms in drug transporters for pharmacotherapy.
- Author
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Kerb R
- Subjects
- Humans, ATP-Binding Cassette Transporters genetics, Drug Therapy, Polymorphism, Genetic
- Abstract
Drug transporters are increasingly recognized as a key determinant of drug disposition and response. It is now widely appreciated that expression of the ATP-dependent efflux transporter, MDR1 (ABCB1, P-glycoprotein), in organs such as the gastrointestinal tract, liver and kidney significantly alters the extent of drug absorption and excretion. Moreover, expression of MDR1 at the level of the blood-brain barrier limits the entry of many drugs into the central nervous system. Given such an important role of MDR1 in the drug disposition process, it is not surprising to see increasing focus on the role of single nucleotide polymorphisms (SNPs) in this transporter as a potential determinant of interindividual variability in drug disposition and pharmacological response. However, drug transport is often the result of the concerted action of efflux and uptake pumps located both in the basolateral and apical membranes of epithelial cells. A growing list of membrane-spanning proteins involved in the in- or outward transport of a large variety of drugs has been recognized and characterized over the past few years in almost all tissues, including organic anion and cation transporters (OAT, OCT, solute carrier family SLC22A), organic anion transport proteins (OATP, solute carrier family SLCO, formerly SLC21A), and MRPs (ABCCs), other members of the ATP-binding cassette family. We are just beginning to appreciate their role for drug delivery and disposition and the contribution of genetic polymorphisms in these transport proteins to interindividual variability in the efficacy and safety for pharmacotherapy. This review summarizes the consequences of inherited differences in drug transport for pharmacotherapy. With the main focus on ABCB1, an update of recent advances is given and clinically relevant examples are used to illustrate how heritable differential drug transport can help to explain individual variability in drug response. The pharmacogenetics of other transporters is briefly introduced.
- Published
- 2006
- Full Text
- View/download PDF
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