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Inhibition of Caffeine Metabolism in Humans by Furanocoumarin-Containing Plant Extracts: in Vivo and in Vitro Studies

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Inhibition of Caffeine Metabolism in Humans by Furanocoumarin-Containing Plant Extracts: in Vivo and in Vitro Studies Inhibition of Caffeine Metabolism in Humans by Furanocoumarin-Containing Plant Extracts: In Vivo and In Vitro Studies by Zeyad Ibrahim Alehaideb B.Sc., King Saud University, 1999 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Department of Biological Sciences Faculty of Science Zeyad Ibrahim Alehaideb 2016 SIMON FRASER UNIVERSITY Spring 2016 Approval Name: Zeyad Ibrahim Alehaideb Degree: Doctor of Philosophy Title: Inhibition of Caffeine Metabolism in Humans by Furanocoumarin-Containing Plant Extracts: In Vivo and In Vitro Studies Examining Committee: Chair: Julian Christians Associate Professor Francis Law Senior Supervisor Professor Margo Moore Supervisor Professor Paul Li Supervisor Professor Department of Chemistry Christopher Kennedy Internal Examiner Professor David Kitts External Examiner Professor Faculty of Land and Food Systems University of British Columbia Date Defended/Approved: April 25, 2016 ii Ethics Statement iii Abstract Caffeine is found at high concentrations in tea, coffee, soft drinks and energy drinks. Daily consumption of caffeinated beverages is considered to be safe but adverse health effects and deaths have been reported in sensitive or overdosed individuals. A variety of furanocoumarin bioactive has been identified in fruits, spices and herbs from plants in the Apiaceous and Rutaceae families. Since caffeinated beverages are often consumed with food, and both are metabolized by the same CYP1A2 enzyme, we hypothesized metabolic inhibition between caffeine and furanocoumarin-containing food or herbs are common in humans. The goals of this thesis were: (a) to compare the pharmacokinetics of caffeine in humans before and after pre-treatment with a furanocoumarin-containing herb, (b) to elucidate the mechanism(s) of caffeine-herb interaction using in vitro incubations containing pure furanocoumarins and human liver microsomes (HLMs), and (c) to predict in vivo herb- caffeine interactions for humans based on in vitro caffeine metabolism data and in vivo furanocoumarin inhibitor concentrations in the liver. Chapter 1 of this thesis is a brief introduction of caffeine and furanocoumarin-containing food and herbs. In chapter 2, major furanocoumarin bioactive in 29 food and herbs are identified and quantified using gas chromatography mass spectrometry and high performance liquid chromatography. Chapter 3 describes the pharmacokinetics of caffeine in humans after administering 200 mg of caffeine orally before and after pre-treatment with an herbal extract. Caffeine clearance in the volunteers decreased 33.7-77.3% with concomitant increases in area-under-the-concentration-time curve after oral consumption of Ammi majus L., Angelica archangelica L., Angelica pubescens Maxim, Cnidium monnieri (L.) Cusson, or Ruta graveolens L. Chapter 4 provides the experimental evidence for irreversible adduct formation between 14C-labeled 8-methoxypsoralen and HLMs. Moreover, the observed caffeine-herb interaction in humans is best explained by mechanism-based inhibition of CYP1A2 enzyme. Chapter 5 demonstrated the use of in vitro-in vivo drug-drug interaction models and an integrated furanocoumarin dose/concentration to predict in vivo furanocoumarin-caffeine herb interaction in humans. Chapter 6 summarizes the conclusions of this thesis. The experimental and modeling approaches described in this study are also useful in predicting in vivo interactions between prescription drugs and dietary supplements or functional food. Keywords: Caffeine; Cytochrome P-450 1A2; Furanocoumarin; Herb-drug interaction; Human liver microsomes; Irreversible inhibition iv Dedication I dedicate this work to all who have supported me v Acknowledgements First and foremost, I would like to express my special appreciation to my academic supervisor, Professor Francis Law, for his continuous support, patience, and motivation during my years with him. I thank my committee members Professor Paul Li and Professor Margo Moore for their insightful comments and encouragement. I also thank my former supervisory committee member Professor Nicholson Russell, who has retired, for his advice and support. I also wish to thank the Saudi Arabian Ministry of National Guard, King Saud Bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Centre, Saudi Arabian Ministry of Higher Education, Saudi Arabian Royal Embassy, and Saudi Arabian Cultural Bureau in Ottawa for their continuous support, understanding, encouragement, and award of scholarship during my studies. Special thanks to my family. Words cannot express how grateful I am to my parents for all the sacrifices that they have made on my behalf. I would also like to thank all of my friends who supported me to strive towards my goal. At the end, I would like to express my greatest appreciation to my wife and daughters who are always my support when needed. vi Table of Contents Approval .............................................................................................................................ii Ethics Statement ............................................................................................................... iii Abstract .............................................................................................................................iv Dedication ......................................................................................................................... v Acknowledgements ...........................................................................................................vi Table of Contents ............................................................................................................. vii List of Tables .....................................................................................................................xi List of Figures.................................................................................................................. xiii List of Equations ............................................................................................................. xvii List of Abbreviations and Acronyms .............................................................................. xviii Glossary ......................................................................................................................... xxii Chapter 1. Introduction ............................................................................................... 1 1.1. Traditional Medicine and Natural Health Products ................................................... 1 1.1.1. What is traditional medicine? ...................................................................... 1 1.1.2. What are natural health products? .............................................................. 1 1.1.3. How much natural health products do we consume? ................................. 2 1.1.4. Regulation of natural health products in Canada ........................................ 3 1.2. Herb-Drug and Food-Drug Interactions .................................................................... 4 1.2.1. Drug pharmacokinetics and pharmacodynamics ........................................ 4 1.2.2. Cytochrome P-450 and drug metabolism.................................................... 4 1.2.3. Definition of drug-drug interactions ............................................................. 6 1.2.4. Methods used to predict drug-drug interactions .......................................... 6 1.2.5. Herb-drug and food-drug interactions can result in adverse health effects ......................................................................................................... 7 1.3. Furanocoumarins ..................................................................................................... 7 1.3.1. The function and structure of furanocoumarins........................................... 7 1.3.2. Plant sources of furanocoumarins .............................................................. 9 1.3.3. How much furanocoumarins do we consume? ......................................... 10 1.3.4. Health effects due to furanocoumarin consumption .................................. 11 1.4. Caffeine .................................................................................................................. 11 1.4.1. The structure and biological effects of caffeine ......................................... 11 1.4.2. Natural sources of caffeine ....................................................................... 12 1.4.3. How much caffeine do we consume? ....................................................... 14 1.4.4. The pharmacokinetics of caffeine in humans ............................................ 15 1.4.5. Health effects due to an increase in caffeine consumption ....................... 16 1.5. Research Objectives .............................................................................................. 19 1.6. References ............................................................................................................. 19 Chapter 2. 8-methoxypsoralen, 5-methoxypsoralen, and Isopimpinellin Concentrations in Extracts From the Apiaceae and Rutaceae Families of Plants ................................................................................... 37 2.1. Abstract .................................................................................................................. 37 2.2. Introduction ...........................................................................................................
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