Clinical Pharmacology

The central research topic of the Clinical Pharmacology section of the Institute (Prof. Dr. Oliver Zolk) is the identification of (genetic) markers which allow prediction of ‘responder’ and ‘non-responder’ to a pharmacotherapy, for example as part of the EU-sponsored project PanCareLIFE. Marked differences in treatment effects between individual patients are frequently observed, leading to treatment failure or undesirable side effects. Unlike standard therapy (“one-size-fits-all”), personalized therapy aims at identifying clinically relevant subpopulations of patients for a targeted treatment. Genetic, molecular, or cellular markers are the basis for selection of patients suitable for a specific therapy. We apply pharmacogenetic tests and advise the physician to adapt the therapy to the individual variations in the genetic profile of the patients.

Projects

Methotrexate pharmacogenetics in childhood ALL

Methotrexate AUCThe purpose of this study was to investigate the pharmacogenetics of methotrexate (MTX) in a large cohort of pediatric patients with acute lymphoblastic leukemia (ALL) using a candidate gene approach. Therefore, 499 children with ALL from the ALL-BFM 2000 trial, who received 1996 courses of MTX at 5 g/m2, were genotyped for 8 single nucleotide polymorphisms (SNPs) in 5 candidate genes of the MTX/folate pathway. Patients' MTX pharmacokinetics, MTX toxicity, and outcome were correlated with the genotypes..... 
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Blood2013121:5145-53

Understanding platinum-induced ototoxicity

Cisplatin ototoxicityPlatinum chemotherapy drugs, such as cisplatin and carboplatin, are the cornerstone of many effective therapeutic protocols for childhood cancer. However, the antitumor efficacy of cisplatin and carboplatin comes at the cost of ototoxicity, which affects at least 60% of pediatric patients. Although ototoxicity is not life threatening, it can have debilitating effects on patients' quality of life. Recently, many initiatives have been launched with the ultimate goal of reducing cisplatin and high-dose carboplatin ototoxicity without compromising antitumor efficacy..... 
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Trends Pharmacol Sci201334:458-69

Current understanding of the pharmacogenomics of metformin

MetaanalysisThe identification of transporters for organic cations involved in the distribution and elimination of the antidiabetic compound metformin marks a milestone in the study of metformin's pharmacokinetics. This was followed by the urgent question of whether genetic variations in these transporters can affect efficacy and risk of adverse events associated with metformin use. After a brief historical review of the discovery of the transporters for cationic drugs, the pharmacogenetics of metformin is discussed here in the light of recent literature.... 
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Clin Pharmacol Ther200986:299-306.

Functional characterization of the human organic cation transporter 2 variant p.270Ala>Ser

Structure of OCT2The organic cation transporter 2 (OCT2, SLC22A2) plays an important role for renal drug elimination. Recent clinical studies indicate an impact of the frequent non-synonymous c.808G>T (p.270Ala>Ser) polymorphism on renal clearance of metformin and the extent of the metformin-cimetidine interaction.... 
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Drug Metab Dispos200937:1312-1318

Activation of negative regulators of the hypoxia-inducible factor (HIF) pathway in human heart failure

The HIF system in human heart failureThe hypoxia-inducible transcription factor HIF is induced early in acute myocardial ischemia in humans, but it is unknown whether this activation of HIF persists during chronic heart failure.... 
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Biochem Biophys Res Commun2008376:315-320


 

Altered Expression of ABC Transporter in the Failing Human Heart

ABCG2 in human heartAdenosine triphosphate-binding cassette (ABC) transporters are involved in energy-dependent transport of substrates across biological membranes. We hypothesized that their expression is altered during human heart failure, suggesting a pathophysiologic basis. Messenger ribonucleic acid quantification of all known ABC transporters revealed multiple alterations in ABC transporter expression in failing human hearts (New York Heart Association classification III-IV) compared to nonfailing controls.... 
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Naunyn Schmiedebergs Arch Pharmacol2008377:231-243

Nano Materials for Gene Therapy

Carbon nanotubeThe lipophilic nature of biological membranes restricts the direct intracellular delivery of potential drugs and molecular probes and makes intracellular transport one of the key problems in gene therapy. Because of their ability to cross cell membranes, single walled carbon nanotubes (SWNTs) are of interest as carriers of biologically active molecules, such as small interfering RNAs (siRNAs).... 
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Biochem Biophys Res Commun2008369:595-602

Cellular Transport Proteins in the Heart

ATP-binding cassette transporterMembers of the ATP-binding cassette (ABC) protein superfamily are integral membrane proteins involved in energy-dependent transport of a wide variety of substrates across biologic membranes. ATP-binding cassette transporters serve as functional barriers against the entry of xenobiotics, for example, in the intestine or at the blood-brain barrier, or contribute to drug excretion, for example, in the kidney or the liver. Many human ABC transporters, such as ABCB1 (P-glycoprotein), ABCC5 (MRP5), or ABCC9 (SUR2), are expressed in the heart, suggesting an important role of these transporters in cardiac drug effects or physiology..... 
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Trends Cardiovasc Med200616:7-15