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3. Phenotype–Genotype Correlation Applying a Cocktail Approach and an Exome Chip Analysis Reveals Further Variants Contributing to Variation of Drug Metabolism.

Author

Böhm, Ruwen, Bruckmueller, Henrike, Oswald, Stefan, Hübenthal, Matthias, Kaehler, Meike, Ehmke, Lena, Höcker, Jan, Siegmund, Werner, Franke, Andre, and Cascorbi, Ingolf

Subjects
DRUG metabolism, MULTIPLE regression analysis, CYTOCHROME P-450 CYP2D6, CYTOCHROME P-450 CYP2C19, PHENOTYPES, CAFFEINE, LOSARTAN
Abstract

Although great progress has been made in the fine‐tuning of diplotypes, there is still a need to further improve the predictability of individual phenotypes of pharmacogenetically relevant enzymes. The aim of this study was to analyze the additional contribution of sex and variants identified by exome chip analysis to the metabolic ratio of five probe drugs. A cocktail study applying dextromethorphan, losartan, omeprazole, midazolam, and caffeine was conducted on 200 healthy volunteers. CYP2D6, 2C9, 2C19, 3A4/5, and 1A2 genotypes were analyzed and correlated with metabolic ratios. In addition, an exome chip analysis was performed. These SNPs correlating with metabolic ratios were confirmed by individual genotyping. The contribution of various factors to metabolic ratios was assessed by multiple regression analysis. Genotypically predicted phenotypes defined by CPIC discriminated very well the log metabolic ratios with the exception of caffeine. There were minor sex differences in the activity of CYP2C9, 2C19, 1A2, and CYP3A4/5. For dextromethorphan (CYP2D6), IP6K2 (rs61740999) and TCF20 (rs5758651) affected metabolic ratios, but only IP6K2 remained significant after multiple regression analysis. For losartan (CYP2C9), FBXW12 (rs17080138), ZNF703 (rs79707182), and SLC17A4 (rs11754288) together with CYP diplotypes, and sex explained 50% of interindividual variability. For omeprazole (CYP2C19), no significant influence of CYP2C:TG haplotypes was observed, but CYP2C19 rs12777823 improved the predictability. The comprehensive genetic analysis and inclusion of sex in a multiple regression model significantly improved the explanation of variability of metabolic ratios, resulting in further improvement of algorithms for the prediction of individual phenotypes of drug‐metabolizing enzymes. [ABSTRACT FROM AUTHOR]

Published
2024
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34. Flupirtine Analogues: Explorative Synthesis and Influence of Chemical Structure on KV7.2/KV7.3 Channel Opening Activity

Author

Surur, Abdrrahman S., Beirow, Kristin, Bock, Christian, Schulig, Lukas, Kindermann, Markus K., Bodtke, Anja, Siegmund, Werner, Bednarski, Patrick J., and Link, Andreas

Subjects
oxidation, Communication, medicinal chemistry, sulfides, structure-activity relationships, ion channels, Communications
Abstract

Neuronal voltage‐gated potassium channels KV7.2/KV7.3 are sensitive to small‐molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands. Clinically, prolonged use of flupirtine as a pain medication is associated with rare cases of drug‐induced liver injury. Thus, safety concerns prevent a broader use of this non‐opioid and non‐steroidal analgesic in therapeutic areas with unmet medical needs such as hyperactive bladder or neonatal seizures. With the goal of studying influences of chemical structure on activity and toxicity of flupirtine, we explored modifications of the benzylamino bridge and the substitution pattern in both rings of flupirtine. Among twelve derivatives, four novel thioether derivatives showed the desired activity in cellular assays and may serve as leads for safer KV channel openers.

Published
2019

43. OATP1B3 is expressed in pancreatic β-islet cells and enhances the insulinotropic effect of the sulfonylurea derivative glibenclamide

Author

Schwabedissen, Henriette E. Meyer zu, Boettcher, Kerstin, Steiner, Tobias, Schwarz, Ute I., Keiser, Markus, Kroemer, Heyo K., and Siegmund, Werner

Subjects
Medical research, Medicine, Experimental, Gene expression -- Research, Polypeptides -- Physiological aspects, Diabetes -- Care and treatment -- Physiological aspects, Hypoglycemic agents -- Dosage and administration -- Physiological aspects, Health
Abstract

Organic anion transporting polypeptide OATP1B3 is a membrane-bound drug transporter that facilitates cellular entry of a variety of substrates. Most of the previous studies focused on its hepatic expression and function in hepatic drug elimination. In this study, we report expression of OATP1B3 in human pancreatic tissue, with the abundance of the transporter localized in the islets of Langerhans. Transport studies using OATP1B3-overexpressing MDCKII cells revealed significant inhibition of the cellular uptake of the known substrate cholecystokinin-8 in the presence of the insulinotropic antidiabetes compounds tolbutamide, glibenclamide, glimepiride, and nateglinide and identified glibenclamide as a novel substrate of OATP1B3. Sulfonylurea derivatives exert their insulinotropic effect by binding to the SUR1 subunit of the [K.sub.ATP] channels inducing insulin secretion in β-cells. Here, we show that transient overexpression of human OATP1B3 in a murine β-cell line (MIN6)-which exhibits glucose and glibenclamide-sensitive insulin secretion--significantly enhances the insulinotropic effect of glibenclamide without affecting glucose-stimulated insulin secretion. Taken together, our data provide evidence that the drug transporter OATP1B3 functions as a determinant of the insulinotropic effect of glibenclamide on the tissue level. Changes in transport activity based on drug-drug interactions or genetic variability may therefore influence glibenclamide efficacy. DOI: 10.2337/db13-1005, The organic anion transporting polypeptides (OATPs/ gene SLCO) belong to the solute carrier (SLC) superfamfly comprising membrane-bound transporters facilitating cellular entry and are characterized by a wide range of diverse [...]

Published
2014
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46. Disposition and Antimuscarinic Effects of the Urinary Bladder Spasmolytics Propiverine: Influence of Dosage Forms and Circadian-Time Rhythms

Author

May, Karen, Westphal, Kristin, Giessmann, Thomas, Wegner, Danilo, Adam, Ulrike, Lerch, Markus M., Oertel, Reinhard, Warzok, Rolf W., Weitschies, Werner, Braeter, Manfred, and Siegmund, Werner

Subjects
Pharmacokinetics -- Research, Parasympatholytic agents -- Dosage and administration -- Research, Health, Research, Dosage and administration
Abstract

Keywords: Propiverine; extended release; circadian rhythm; ABCC2 570 Pharmacokinetics and PharmacodynamicsDisposition and Antimuscarinic Effects of the Urinary Bladder Spasmolytics Propiverine: Influence of Dosage Forms and Circadian-Time Rhythms SAGE Publications, Inc.200810.1177/0091270008315314 [...]

Published
2008
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49. The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide

Author

Hermann, Robert, Siegmund, Werner, Giessmann, Thomas, Westphal, Kristin, Weinbrenner, Anita, Hauns, Bernhard, Reutter, Felix, Lahu, Gezim, Zech, Karl, and Bethke, Thomas D.

Subjects
Altana Pharma AG, Esterases -- Analysis, Tuberculosis -- Analysis, Anti-inflammatory drugs -- Dosage and administration -- Analysis, Antiasthmatic agents -- Dosage and administration -- Analysis, Pharmaceutical industry -- Analysis, Health, Analysis, Dosage and administration
Abstract

This open-label, randomized, 3-period crossover study evaluated the pharmacokinetic interaction potential of roflumilast and budesonide following repeated coadministration to healthy male subjects (N = 12). Treatments consisted of oral roflumilast [...]

Published
2007

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