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Pharmacodynamics of Enzyme Induction and Its Consequences for Substrate Elimination

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Pharmacodynamics of Enzyme Induction and Its Consequences for Substrate Elimination Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 52 Pharmacodynamics of Enzyme Induction and its Consequences for Substrate Elimination MATS O. MAGNUSSON ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 UPPSALA ISBN 978-91-554-6860-6 2007 urn:nbn:se:uu:diva-7812 ! "##$ %& ' ( ) ' ' *( ( +! ' *( ,- .( (- ) /- "##$- *( ' 0 1 2 3 ' 0 - 4 - &"- 5" - - 26 7$8979&&9585#95- 0 1 ( ( ( ' 1-2' ( '' 1 ( ' ) ( ) - 2 (' ' : ) ) - .( ( ( '9' ' ( 1 ( ( ; ' ( ) ) ( ( ( < ( - .( ' ( ( ) ( ; ' 1 ( 3 ( ( ' - ' ) ' ( ( ' ( ' ( ' ( - 0 1 ( 1 ) ( ( (- 4 ) ( ( ) ( ( ; ' ( 1 6=49$& ( 1 - .( 3 ' ( ) ( ( ; ) ) ' 9 ( ) ( ' ( ) ) ' - .( ' ( ) - 2 ( ' ' ( ( ( ; ' ( ) ) ( '' 1 - .( ( ) ) ( ) 1 ( - 2 ( ' ) ( ' ( 1 ( ( ( 1 - .( ) ( ( '9 ' >*%4 >*4" - .( ; ' ( 1 ( ) ( - .( ( ) ' ( 3 ' - *( ; *( 0 1 . . ( 9 ) 6/60 !" # $ # $ # $ % &'(# # )*'&+,- # ? /- ) "##$ 26 5&957" 26 7$8979&&9585#95 9$8" +( @@ -;-@ A B 9$8", Brilliant thoughts under the infl uence of Diet Coke Till min familj, mest mamma! Papers Discussed Th is thesis is based on the following papers, which will be referred to in the text by the Roman numbers assigned below. I M. O. Magnusson and R. Sandström. Quantitative analysis of eight testosterone metabolites using column switching and liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 18: 1089-94 (2004). Reproduced with permission. © 2004 Wiley & Sons Limited. II M. O. Magnusson, P-H. Zingmark, B. Fransson, M. O. Karlsson and, R. Sandström. A mechanistic model describing the impact of carbamazepine on the pharmacokinetics of clomethiazole and its metabolite NLA-715. In manuscript. III M. O. Magnusson, M. O. Karlsson, and R. Sandström. A mechanism- based integrated pharmacokinetic enzyme model describing the time course and magnitude of phenobarbital-mediated enzyme induction in the rat. Pharm Res. 23: 521-32 (2006). Reproduced with permission. © 2006 Springer Science and Business Media. IV M. O. Magnusson, M-L. Dahl, J. Cederberg, M. O. Karlsson, and R. Sandström. Pharmacodynamics of enzyme induction attributable to carbamazepine treatment using midazolam, caff eine and digoxin as probes for CYP3A, CYP1A2 and P-glycoprotein. In manuscript. Contents Introduction .......................................................................................11 Background .................................................................................................11 Biotransformation of Xenobiotics ...............................................................12 Cytochrome P450 ..................................................................................... 12 Phase II Metabolism ..................................................................................12 Effl ux Transporters .....................................................................................13 Overlapping Substrate Specifi city............................................................... 13 Mechanisms of Enzyme Induction .............................................................13 Nuclear Receptors and Inducible Proteins .................................................14 Drug-drug Interactions ...............................................................................14 Inducing Drugs ......................................................................................... 14 Th e Consequences of Enzyme Induction .................................................. 14 Interactions Caused by Enzyme Induction .................................................15 Interactions Caused by P-glycoprotein Induction ..................................... 16 Enzyme Activity and Protein Abundance ...................................................16 In Vitro Techniques ....................................................................................16 In Vivo Techniques ....................................................................................16 In Vitro-In Vivo Extrapolation .................................................................... 17 Pharmacodynamics of Enzyme Induction ...................................................17 Half-life of the Induced Enzyme ................................................................18 Pharmacokinetics of the Inducing Agent ................................................... 19 Th e Stimulus Function .............................................................................. 19 Delayed Commencement ................................................................................. 20 Induction Magnitude-Baseline Correlation ...............................................21 Pharmacokinetics of the Aff ected Drug ......................................................21 Non-linear Mixed Eff ect Modelling of Induction ........................................22 Mechanistic Models ...................................................................................22 Non-linear Mixed Eff ect Modelling ...........................................................22 Th e Structure of the Model ........................................................................23 Characteristics of Compounds ....................................................................23 Inducing Agents ........................................................................................ 23 Phenobarbital ................................................................................................... 23 Carbamazepine ................................................................................................. 24 Probe Substances ....................................................................................... 24 Testosterone ...................................................................................................... 24 Resorufi n ..........................................................................................................24 Midazolam ....................................................................................................... 24 Caff eine ............................................................................................................24 Digoxin ............................................................................................................ 24 Aims ...................................................................................................25 Materials and methods .......................................................................26 Experimental Procedures Preclinical Investigation (Paper III) .....................26 Animals ..................................................................................................... 26 Dosage and Sampling ................................................................................ 26 Microsome Preparation and Incubations ....................................................26 Estimation of the Activity of the CYP-enzymes ......................................... 27 Experimental ProceduresClinical Investigations (Papers II and IV) .............27 Carbamazepine-Clomethiazole Interaction Study (Paper II) ...................... 27 Carbamazepine–Drug Cocktail Interaction Study (Paper IV) .................... 27 Chemical Analysis .......................................................................................28 Eight Metabolites of Testosterone (Papers I and III) ...................................28 Phenobarbital and Resorufi n (Paper III) .................................................... 28 Clomethiazole, NLA-715 and Carbamazepine (Paper II) ...........................29 Carbamazepine and the Cocktail of Drugs (Paper IV) ............................... 29 Validation of Chemical Assays ................................................................... 29 Data Evaluation ..........................................................................................30 Modelling Procedures .................................................................................31 Model for Carbamazepine-Clomethiazole Interaction (Paper II) ................31 Model for Phenobarbital Induction (Paper III) .......................................... 32 Model for Carbamazepine-Drug Cocktail Interaction (Paper IV) .............. 32 Digoxin ............................................................................................................ 33 Carbamazepine ................................................................................................. 33 Midazolam ....................................................................................................... 33 Caff eine ............................................................................................................34 Results and discussion ........................................................................35 Quantifi cation of Eight Metabolites of Testosterone (Paper I).....................35 Assessment of Enzyme Activity ...................................................................37 In Vitro .....................................................................................................
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