Prediction of Transport, Pharmacokinetics, and Effect of Drugs
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Prediction of Transport, Pharmacokinetics, and Effect of Drugs Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Felix Hammann aus Deutschland Basel, 2009 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von: Prof. Dr. Jürgen Drewe Prof. Dr. Jörg Huwyler Basel, den 23. Juni 2009 ____________________________ Prof. Dr. Eberhard Parlow Dekan “Realism can break a writer’s heart.” Salman Rushdie, in ‘Shame’ “Elämä on laiffii.” Matti Nykänen “Computer says: no.” David Walliams Acknowledgments Acknowledgments The three years that went into this thesis were eventful, to say the least, and I can hardly imagine any other place where work as a Ph.D. student would have been more rewarding, productive, and fun. Of course, my supervisor Prof. Dr. Jürgen Drewe deserves the lion’s share of credit for this. His scientific creativity, his ability to look beyond biomedicine, and his unique talent to build and foster a focused yet relaxed atmosphere in a crowded lab with people of diverse backgrounds are probably one of a kind. Dr. Heike Gutmann is the head of lab anyone would wish for. Her unpretentious and warm personality often made me forget she was actually my direct boss. I will miss working with her as much as I will miss the coffee breaks. Uschi Behrens has often been referred to as the ‘gem of Lab 411’. Rightly so. She shared her competence, skill, and long experience at the bench patiently and more often than not showed me where the pointed end of the pipette was. Fondly remembered for many of the same reasons are those who shared the bench with me. Dr. Angelika Graber-Maier and Dr. Birk Poller were uncomplicated, supportive, and have a sense of humor which generally made work a blast. I will certainly remember the field trips to the Black Forest and to Paris, be that for the Dalton gang or Louis de Funès. Clinical work was always together with Dr. Oliver Kummer, an apt clinician and colorful personality in and out the workplace, to whom I owe many insights (such as the proper spelling of 旨味). Thanks go to the members of the defense committee. Prof. Dr. Jörg Huwyler was kind enough to participate in the examination and Prof. Dr. Peter Hauser acted as chairman. During these three years, I had a number of supporters who took me into their departments: Prof. Dr. Dr. Stephan Krähenbühl who heads the Dept. of Clinical Pharmacology and Toxicology. Dr. Christoph Helma, to whom I am grateful not only for the time at the University of Freiburg but also for essential help in software design and understanding the principles of QSAR. And, of very special note, Prof. Dr. Christoph Beglinger, head of the Department of Gastroenterology, who generously enabled me on numerous occasions to continue the work. I thank him as well as his scientific team, Robert Steinert and Anne Christin Gerspach. Klingelbergstrasse was where I finally wrapped things up with Filterkaffee and a dog filled with helium. Dr. Dr. Petr Hruz must be mentioned for getting me started in the first place. He has been supportive and collegial in a way I could not have expected. In the same vein, I am grateful to Dr. Christian Zimmermann who helped greatly in securing grants. Industrious and diligent people contributed data in the course of their diploma and medical theses. These are Ursi Jecklin, Nadine Vogt, Stefania Guercioni (during the nicotine trial with Prof. Dr. Georgios Imanidis), and Dr. Ulli Baumann. Special mention should also go to the many people around the lab and the various departments: Dr. Michael Bodmer, Dr. Yolanda Brauchli, Dr. Sabin Egger, Evelyne Furger, Dr. Manuel Haschke, Zorana Radic, Evelyne Rudin, Bea Vetterli. Finally, family and friends were most patient with me: most notably my parents, Barbara and Heinz, who continuously supported me throughout the thesis and the work before. And so did Helen, not only by proofreading and making coffee. – i – Abbreviations Abbreviations ABC ................................................................. ATP Binding Cassette ABD ................................................................. ATP Binding Domain ADME .............................................................. Absorption, Distribution, Metabolism, and Excretion AI ..................................................................... Artificial Intelligence ARNT............................................................... Aryl Hydrocarbon Receptor Nuclear Translocator ASCII ............................................................... American Standard Code for Information Interchange ATP.................................................................. Adenosine Triphosphate ANN ................................................................. Artificial Neural Network BBB ................................................................. Blood-Brain Barrier BCRP............................................................... Breast Cancer Resistance Protein CAR ................................................................. Constitutive Androstane Receptor CART............................................................... Classification And Regression Trees CCR................................................................. Corrected Classification Rate CHAID ............................................................. Chi-square Automatic Interaction Detector CI ..................................................................... Confidence Interval CNS ................................................................. Central Nervous System CPSA............................................................... Charged Polar Surface Area CV.................................................................... Cross Validation CYP ................................................................. Cytochrome P DBS ................................................................. Drug Binding Site DME................................................................. Drug Metabolizing Enzyme DTI................................................................... Decision Tree Inference HBA ................................................................. Hydrogen Bond Acceptor HBD ................................................................. Hydrogen Bond Donor HTTP ............................................................... Hypertext Transfer Protocol HTS ................................................................. High-Throughput Screening IC50 .................................................................. Mean Inhibitory Concentration ID3 ................................................................... Iterative Dichotomizer 3 kNN.................................................................. k-nearest Neighbor LD50 ................................................................. Mean Lethal Dose LOO ................................................................. Leave-One-Out Cross-validation MDL ................................................................. Minimum Description Length MDR ................................................................ Multi-Drug Resistance ML.................................................................... Machine Learning MLP ................................................................. Multi-Layer Perceptron MRP................................................................. Multidrug Resistance associated Protein NSAID.............................................................. Non-Steroidal Anti-Inflammatory Drug OAT ................................................................. Organic Anion Transporter OR ................................................................... Odds Ratio – ii – Abbreviations P-gp ................................................................. P-glycoprotein PPARα............................................................. Peroxisome Proliferator Activated Receptor α PXR ................................................................. Pregnane X Receptor QSAR .............................................................. Quantitative Structure Activity Relationship QPSR .............................................................. Quantitative Structure Property Relationship RF.................................................................... Random Forest ROC................................................................. Receiver Operating Characteristic RXR ................................................................. Retinoid X Receptor SABL ............................................................... Smallest Associated Binary Label SJW ................................................................. St. John’s Wort SMARTS.......................................................... SMILES Arbitrary Target Specification SMILES ........................................................... Simple Molecular Input Line Specification SNP ................................................................. Single Nucleotide Polymorphism SQL ................................................................. Structured Query Language SSSR............................................................... Smallest Subset of Rings SVM................................................................. Support Vector Machines TPSA ............................................................... Total Polar Surface Area UDP ................................................................. Uridine diphosphate