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Inhibition of CYP1A2-Mediated Drug Metabolism in Vitro and in Humans

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Inhibition of CYP1A2-Mediated Drug Metabolism in Vitro and in Humans Department of Clinical Pharmacology University of Helsinki Finland Inhibition of CYP1A2•mediated drug metabolism in vitro and in humans With special emphasis on rofecoxib and other NSAIDs Marjo Karjalainen ACADEMIC DISSERTATION To be presented, with the permission of the Medical Faculty of the University of Helsinki, for public examination in Auditorium 2 of Biomedicum Helsinki, Haartmaninkatu 8, on August 15th, 2008, at 12 noon. Helsinki 2008 Supervisors: Docent Janne Backman, MD Department of Clinical Pharmacology University of Helsinki Helsinki, Finland Professor Pertti Neuvonen, MD Department of Clinical Pharmacology University of Helsinki Helsinki, Finland Reviewers: Professor emeritus Heikki Vapaatalo, MD Institute of Biomedicine, Pharmacology University of Helsinki Helsinki, Finland Docent Miia Turpeinen Department of Pharmacology and Toxicology University of Oulu Oulu, Finland Opponent: Professor Ilari Paakkari Institute of Biomedicine, Pharmacology University of Helsinki Helsinki, Finland ISBN 978•952•92•4143•9 (paperback) ISBN 978•952•10•4777•0 (PDF, http://ethesis.helsinki.fi) Helsinki 2008, Yliopistopaino To Jesse To my family To Ali TABLE OF CONTENTS TABLE OF CONTENTS ABBREVIATIONS..................................................................................................................... 6 n LIST OF ORIGINAL PUBLICATIONS.......................................................................... 8 n ABSTRACT................................................................................................................................... 9 n INTRODUCTION...................................................................................................................... 11 n REVIEW OF THE LITERATURE..................................................................................... 12 1. Drug metabolism and transport… .................................................................................... 12 1.1. Phase I reactions and enzymes........................................................................ 13 1.1.1. The CYP1 family........................................................................... 13 1.1.2. The CYP2 family........................................................................... 15 1.1.3. The CYP3 family........................................................................... 17 1.2. Phase II reactions and enzymes....................................................................... 19 1.3. Drug transporters............................................................................................. 20 1.3.1. Uptake transporters........................................................................ 20 1.3.2. Efflux transporters......................................................................... 21 1.4. Pharmacogenetics............................................................................................ 22 1.5. In vitro systems for studying drug metabolism............................................... 23 2. Inhibition of drug metabolism.......................................................................................... 25 2.1. Reversible inhibition....................................................................................... 25 2.2. Quasi•irreversible and irreversible inhibition................................................. 26 2.3. Structures of typical CYP1A2 inhibitors........................................................ 26 3. Induction of drug metabolism........................................................................................... 28 4. In vitro•in vivo prediction.............................................................................................. 29 5. Compounds....................................................................................................................... 30 5.1. Rofecoxib........................................................................................................ 30 5.2. Tolfenamic acid............................................................................................... 31 5.3. Celecoxib......................................................................................................... 32 5.4. Tizanidine........................................................................................................ 33 5.5. Caffeine........................................................................................................... 34 5.6. Other drugs...................................................................................................... 35 n AIMS OF THE STUDY........................................................................................................... 39 n MATERIALS AND METHODS.......................................................................................... 40 1. In vitro studies (Studies II, III, IV and V)........................................................................ 40 1.1. Microsomes..................................................................................................... 40 1.2. Incubation conditions...................................................................................... 40 1.2.1. Screening, and IC50 and Ki determinations.................................... 40 1.2.2. Evaluation of metabolism•dependent inhibition............................ 41 1.3. Measurement of drug concentrations.............................................................. 42 1.4. Data analysis................................................................................................... 42 2. In vitro•in vivo predictions (Studies II, III, IV and V)..................................................... 44 2.1. Competitive inhibitor ..................................................................................... 44 2.2. Mechanism•based inhibitor............................................................................. 44 3. Studies in vivo in humans (Studies I, III and IV)............................................................. 45 3.1. Subjects .......................................................................................................... 45 3.2. Study design.................................................................................................... 45 TABLE OF CONTENTS 3.3. Sampling.......................................................................................................... 46 3.4. Determination of drug concentrations in plasma and urine............................ 46 3.4.1. Tizanidine and its metabolites....................................................... 46 3.4.2. Rofecoxib, tolfenamic acid and celecoxib..................................... 47 3.4.3. Caffeine and paraxanthine............................................................. 47 3.5. Pharmacokinetic method................................................................................. 48 3.6. Pharmacodynamics.......................................................................................... 48 3.7. Statistical analysis........................................................................................... 49 n RESULTS....................................................................................................................................... 50 1. In vitro studies (Studies II, III, IV and V)........................................................................ 50 1.1. Inhibition of phenacetin metabolism............................................................... 50 1.2. The effect of preincubation on the inhibition potential................................... 50 1.3. Inactivation of CYP1A2 by rofecoxib............................................................ 50 1.4. The effect of albumin on the inhibitory effect of tolfenamic acid.................. 52 2. In vitro•in vivo predictions (Studies II, III, IV and V)..................................................... 53 2.1. Competitive inhibition model....................................................................... 53 2.2. Mechanism•based inhibition model............................................................. 53 3. In vivo studies (Studies I, III and IV)............................................................................... 55 3.1. The effect of rofecoxib, tolfenamic acid and celecoxib.................................. 55 3.1.1. Tizanidine pharmacokinetics......................................................... 55 3.1.2. Caffeine test................................................................................... 55 3.1.3. Tizanidine pharmacodynamics...................................................... 57 3.2. Rofecoxib, tolfenamic acid and celecoxib concentrations.............................. 58 n DISCUSSION............................................................................................................................... 59 1. Methodological considerations......................................................................................... 59 1.1. In vitro studies................................................................................................. 59 1.2. In vitro•in vivo predictions.............................................................................. 60 1.3. In vivo studies… .............................................................................................. 61 2. The effect of rofecoxib on CYP1A2 activityin vitro and in vivo.................................... 63 3. The effect of tolfenamic acid on CYP1A2 activity in vitro and in vivo..........................
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