Research report 2009 of the faculty of medicine of the friedrich-alexander-university erlangen-nürnberg

Institute of Experimental and Clinical Pharmacology
and Toxicology
Chair of Clinical Pharmacology and Clinical toxicology
the following topics, which are funded e.g. and oAtP1B3-mediated pravastatin uptake. by the German Research Council (DFG) and In vivo, this reduced hepatic uptake may lead the German Cancer Aid, are in the focus of to elevated pravastatin plasma concentrations our studies: uptake and efflux transporters for with an increased risk of adverse drug reac- drugs, genetic determinants of drug effects tions. A second study showed that frequently (pharmacogenomics), drug metabolism (cyto- prescribed oral antidiabetic drugs inhibit oAtP- chrome P450 enzymes), drug uptake in tumors, head of institute
cardiovascular pharmacology and risk factors, alterations of the L-arginine-No-metabolism.
Expression and function of uptake trans-
porters in gastrointestinal tract
the knowledge on the importance of oAtP up- take transporters for drug transport, physiolo- Molecular characterization of drug
gy and pathophysiology in the human gastro- transporters
intestinal tract is still limited. therefore, stud- research Focus
ies regarding the expression and function of • Molecular characterization of drug trans- transporter proteins located in distinct plas- oAtPs in human stomach and intestine were ma membrane domains are important for up- performed. In collaboration with the University • Expression and function of uptake transport- take, distribution and excretion of drugs and of Kentucky, (Lexington, KN, UsA), the Univer- drug metabolites. therefore, modulation of sity of Western ontario (London, ontario, Can- • Pharmacogenetics of cardiovascular drugs transport function may result in adverse drug ada) and the Vanderbilt University (Nashville, • Molecular and clinical characterisation reactions (ADR). two molecular mechanisms tN, UsA; Prof. W. Lee und Prof. R. B. Kim) the can account for such modulations of transport expression of the oAtP1B3 in multiple colon function. First, variations in transporter genes carcinoma samples was detected. Moreover, (polymorphisms) may result in mutated trans- oAtP1B3 mediated apoptosis resistance in sev- porter proteins with altered transport kinet- eral colon carcinoma cell lines after treatment structure of the institution
ics. second, one drug can influence the trans- with the antineoplastic agents oxaliplatin and port kinetics of a second coadministered drug the Chair of Clinical Pharmacology and Clini- if both are substrates for one transport pro- A further member of the human oAtP-family cal toxicology forms together with the Chair tein (transporter-dependent drug-drug inter- is the prostaglandin transporter oAtP2A1. the of Pharmacology and toxicology and the Do- actions). the molecular characterizations of transport of prostaglandins from the extracel- erenkamp-Professorship of Innovations in Ani- both processes are in the focus of our studies.
lular space to the cytosol by oAtP2A1 contrib- mal and Consumer Protection the Institute of organic Anion transporting Polypeptide 1B1 utes to the termination of prostaglandin ef- Experimental and Clinical Pharmacology and (oAtP1B1) is an important uptake transport- fects. In collaboration with the Institute of Pa- toxicology. the position of the executive direc- er located in the basolateral hepatocyte mem- thology (Prof. K. U. Amann, Dr. t. Rau) it was tor of the Institute rotates between the Chair brane mediating the uptake of several endoge- possible to show the localization of oAt2A1 in of Pharmacology and toxicology (Prof. A. Lud- nous compounds and drugs from the portal ve- parietal cells and deep glands of corpus and an- wig) and the Chair of Clinical Pharmacology nous blood into the liver. In a cooperation with trum of human stomach, respectively. Further- and Clinical toxicology (Prof. M. Fromm) on a the University of Greifswald we could demon- more, using oAtP2A1-overexpressing cell lines strate that the cholesterol-lowering drug ezet- we were able to demonstrate that NsAIDs (non 35 persons are working at the Chair with 10 of imibe inhibited oAtP1B1-mediated uptake and steroidal anti-inflammatory drugs) can stimu- them being funded by extramural sources. In that the metabolite ezetimibe-glucuronide is a late or inhibit the function of oAtP2A1. such July 2008 a Professor of Clinical Pharmacology substrate of this transporter. Furthermore, we functional modifications may contribute to (W2) was appointed. Research is conducted by have demonstrated that a frequent polymor- NsAID-induced side effects such as ulcerations 6 scientists with 4 of them being specialists in phism of the oAtP1B1 protein (variant oAt- or bleeding in the human gastric mucosa.
clinical pharmacology, 10 MD or PhD students P1B1*5) is associated with reduced uptake rates for ezetimibe-glucuronide compared to the Pharmacogenetics of cardiovascular drugs
the groups at the Chair of Clinical Pharmacol- wild type protein. these results are in agree- ogy and Clinical toxicology investigate mech- ment with results from a clinical study con- Cardiovascular diseases are the most common, anisms underlying interindividual differences and cardiovascular drugs belong to the most in drug effects using molecular and cellular bi- oAtP1B1, together with the oAtP family mem- frequently prescribed drugs. their use contrib- ology as well as clinical studies. the Chair has bers oAtP1B3 and oAtP2B1 that are also ex- utes to reduced mortality from cardiovascular excellent opportunities for drug analytics and pressed in human hepatocytes were in the events, for example dual antiplatelet inhibition a clinical trial unit. In addition, a drug informa- focus of studies investigating transporter-me- with Ass and clopidogrel significantly reduces tion service is available for the physicians of the diated drug-drug interactions. First, we could the risk of fatal coronary stent thrombosis after University Hospital and for external physicians.
demonstrate that macrolides inhibit oAtP1B1- PCI. However, there are marked differences in 44 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) the treatment effects between individual pa-tients with treatment failure or enhanced tox-icity occurring in some patients. In this project genetic variations in genes involved in drug transport or metabolism that cause interindi-vidual differences in response to cardiovascular drugs are investigated. In a collaborative proj-ect with the Heart Centre Bad Krozingen the as- Expression of the human uptake transporter OCT2 (green) in HEK293 cells sociation of polymorphisms in drug transport-ers and cytochrome P450 enzymes with the in-hibitory effect of clopidogrel on platelet aggre-gation was investigated.
Another study focused on the impact of gen-der and genetic differences in genes involved failure in cardiovascular medicine, with a spe- Lieb W, Benndorf RA, Benjamin EJ, sullivan LM, Maas R, Xanthakis V, schwedhelm E, Aragam J, schulze F, Boeger in transport and metabolism of drugs on the cial focus on the prevention of thromboembol- RH, Vasan Rs (2009) Plasma asymmetric dimethylarginine, pharmacokinetics of the diuretic torasemide. ic events. Related health services research proj- L-arginine and left ventricular structure and function in Moreover, in a collaborative project with the ects are directed at real life problems in trans- a community-based sample. Atherosclerosis, 204: 282-7 Department of Medicine 4 – Nephrology and lating knowledge and implementing guidelines Hypertensiology (University Hospital Erlangen) international cooperation
we investigate a potential association of poly- Prof. Carmine Zoccali, Renal Dialysis transplantation and morphisms in catecholamine transporter genes Hypertension Unit & Institute of Bio-Medicine of the Na-tional Research Council, Reggio Calabria, Italy with the diagnosis of essential hypertension.
Prof. Ramachandran Vasan, Framingham Heart study, UsA Molecular and clinical characterisation
the Chair coordinates the interdisciplinary lec- Prof. Jean-Luc Cracowski, INsERM Grenoble, France of therapeutic targets in the
ture series and seminar Clinical Pharmacology L-arginine-NO-nitrate pathway
/ Pharmacotherapy for medical students apply- research equipment
ing problem-based learning. In addition, we Applied Biosystems API 4000 Ms/Ms system Package A major focus of the group is the experimental teach students of dental medicine, molecular and clinical characterization of new cardiovas- medicine, pharmacy and medical process man- cular risk factors as potential targets for ther- agement in Clinical Pharmacology by lectures, apeutic interventions. Presently we study the seminars and practical exercises. students of regulation of the L-arginine-No-nitrate path- pharmacy are welcome to work with us during way by endogenously formed compounds such as ADMA and L-NMMA and the metabolic fate of these compounds. For in vitro and in vivo in-vestigations new isotope- and mass spectrom- selected Publications
etry-based methods are developed. In a DFG Zolk o, Jacobi J, Pahl A, Fromm MF, schmieder RE (2007) funded project and in cooperation with col- MDR1 genotype-dependent regulation of the aldosterone system in humans. Pharmacogenet Genomics, 17: 137-44 leagues at the Department of Medicine 4 – Ne-phrology and Hypertensiology (University Hos- Bachmakov I, Glaeser H, Fromm MF, Koenig J (2008) Interaction of oral antidiabetic drugs with hepatic uptake pital Erlangen) we investigate the biologic ef- transporters: focus on organic anion transporting polypep- fects of disturbed methylarginine metabolism tides and organic cation transporter 1. Diabetes, 57: 1463-9 on vascular function in animal models and ex- Gradhand U, Lang t, schaeffeler E, Glaeser H, tegude H, perimental studies. the experimental inves- Klein K, Fritz P, Jedlitschky G, Kroemer HK, Bachmakov I, tigations are complemented by clinical and Anwald B, Kerb R, Zanger UM, Eichelbaum M, schwab M, Fromm MF (2008) Variability in human hepatic MRP4 population-based studies performed in coop- expression: influence of cholestasis and genotype. Pharma- eration with the Department of Medicine 2 – Cardiology and Angiology and international Lee W, Belkhiri A, Lockhart AC, Merchant N, Glaeser H, Har- partners at the Framingham Heart study (UsA) ris EI, Washington MK, Brunt EM, Zaika A, Kim RB, El-Rifai and at the Institute of Bio-Medicine of the Na- W (2008) overexpression of oAtP1B3 confers apoptotic resistance in colon cancer. Cancer Res, 68: 10315-23 tional Research Council (Italy). With these part- trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, ners we presently investigate causes and long Valina CM, stratz C, schmiebusch P, Bestehorn HP, Buettner term clinical effects of elevated plasma con- HJ, Neumann FJ (2008) Cytochrome P450 2C19 681G>A centrations of ADMA and related substances.
polymorphism and high on-clopidogrel platelet reactivity In further projects we study genetic and bio- associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or chemical/pharmacological causes of treatment bare-metal stents. J Am Coll Cardiol, 51: 1925-34 Research Report of the Medical Faculty of the University Erlangen-Nürnberg (Reporting Period 2007 – 2008) 45


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