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Fucus Vesiculosus 25 I.4 UNIVERSIDADE DA BEIRA INTERIOR Ciências Nonclinical assessment of the potential for herb-drug interactions between herbal extracts present in weight loss supplements and lamotrigine Sandra Cristina do Espírito Santo Ventura Tese para obtenção do Grau de Doutor em Bioquímica (3º ciclo de estudos) Orientador: Prof. Doutor Gilberto Alves Coorientador: Prof. Doutor Amílcar Falcão Covilhã, março de 2019 The experimental work presented in this thesis was carried out at the Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior (CICS-UBI), under the scientific supervision of Professor Gilberto Lourenço Alves (CICS-UBI, Covilhã) and Professor Amílcar Celta Falcão Ramos Ferreira (Center for Neuroscience and Cell Biology, Coimbra). O trabalho experimental apresentado nesta tese foi realizado no Centro de Investigação em Ciências da Saúde, da Faculdade de Ciências da Saúde, da Universidade da Beira Interior (CICS-UBI), sob a orientação científica do Professor Doutor Gilberto Lourenço Alves (CICS-UBI, Covilhã) e do Professor Doutor Amílcar Celta Falcão Ramos Ferreira (Centro de Neurociências e Biologia Celular, Coimbra). iii The work underlying the present thesis was supported by FEDER funds through the POCI - COMPETE 2020 - Operational Programme Competitiveness and Internationalisation in Axis I - Strengthening research, technological development and innovation (Project POCI-01-0145- FEDER-007491) and National Funds by FCT - Foundation for Science and Technology (Project UID/Multi /00709/2013). O trabalho subjacente à presente tese teve o apoio financeiro de fundos FEDER através do POCI – COMPETE 2020 - Programa Operacional Competitividade e Internacionalização no Eixo I - Reforçar a investigação, o desenvolvimento tecnológico e a inovação (Project POCI-01-0145-FEDER-007491) e fundos Nacionais pela FCT – Fundação para a Ciência e a Tecnologia (Project UID/Multi /00709/2013). v Não sou nada. Nunca serei nada. Não posso querer ser nada. À parte isso, tenho em mim todos os sonhos do mundo (...) O mundo é para quem nasce para o conquistar E não para quem sonha que pode conquistá-lo, ainda que tenha razão. Tenho sonhado mais que o que Napoleão fez. Tenho apertado ao peito hipotético mais humanidades do que Cristo, Tenho feito filosofias em segredo que nenhum Kant escreveu. Mas sou, e talvez serei sempre, o da mansarda Ainda que não more nela; Serei sempre o que não nasceu para isso (...) Álvaro de Campos vii Agradecimentos Agradeço ao Professor Doutor Gilberto Lourenço Alves, pela sua sabedoria e por ser um exemplo de dedicação ao saber, à investigação e ao conhecimento, pela persistência e paciência em todas as horas de trabalho, pela orientação e por todas as palavras de incentivo e motivação ... será sempre e sem dúvida um pilar na minha formação. O meu eterno agradecimento! Agradeço ao Professor Doutor Amílcar Falcão, pela partilha, pelo seu notável contributo científico e pelo muito que me honra em ser coorientador do meu trabalho. Agradeço ao Professor Doutor Márcio Rodrigues, pois sem a sua partilha este projeto não tinha chegado a bom porto, por ser um indiscutível exemplo de dedicação à ciência e investigação. Aos colegas do CICS, que percorreram os mesmos corredores, as mesmas salas e laboratórios, que partilharam os momentos de alegria, as mesmas dificuldades... a todos vós, o meu muito obrigada! Aos amigos e colegas da Escola Superior de Saúde, do Instituto Politécnico da Guarda, pelo caminho difícil que trilhei com a vossa ajuda, a maioria das vezes impercetível aos olhos dos outros, o meu muito obrigada! À minha mãe Trindade, pelo apoio, pela infindável ajuda, pelo amor incondicional, pela sua capacidade em resolver todos os meus problemas. Obrigada mãe! Ao meu pai António José, pelo exemplo de Homem, que me acompanhou em muitos caminhos e que me ensinou a ser mais humilde! Obrigada pai! ix Ao meu marido Tiago, que me acompanhou nas horas complicadas, pelas dificuldades que passámos e pelos muros que se quebraram.... Obrigada por seres meu companheiro! À Iris e Joana, as minhas queridas filhas, quero agradecer os abraços, mesmo após tantas horas de distância, porque quis que tivessem orgulho em mim e porque trabalhei para vos fazer um pouco mais felizes. Amar-vos é um privilégio! x Table of contents xi Table of contents Resumo xix Abstract xxiii List of Figures xxvii List of Tables xxxv List of Abbreviations xli List of Publications xlvii CHAPTER I. General introduction: plants, obesity and epilepsy 1 I.1. Plants: the medicines from nature 3 I.1.1. Regulatory perspective on the use of herbal medicines 5 I.2. Herb-drug interactions 7 I.2.1. Pharmacokinetic herb-drug interactions 8 I.2.2. Pharmacodynamic herb-drug interactions 12 I.2.3. Herb-drug interactions evaluation 13 I.3. Plants, overweight and obesity 14 I.3.1. Paullinia cupana 17 I.3.2. Garcinia cambogia 20 I.3.3. Citrus aurantium 23 I.3.4. Fucus vesiculosus 25 I.4. Epilepsy and pharmacotherapeutic approaches 27 I.4.1. Obesity and its association with epilepsy 28 I.4.2. Pharmacotherapy in epilepsy 30 I.4.2.1. Selecting the best therapeutic option 34 I.4.2.2. Enzyme induction 38 I.4.2.3. Enzyme inhibition 39 I.4.2.4. Herb-drug interactions involving antiepileptic drugs 39 I.5. Lamotrigine 41 I.5.1. Physicochemical properties 43 I.5.2. Pharmacokinetic and pharmacodynamic properties 44 I.5.3. Therapeutic drug monitoring of lamotrigine 47 I.6. Aims of this thesis 48 CHAPTER II. Bioanalysis of lamotrigine 51 II.1. Bioanalytical methods for lamotrigine quantification 53 II.1.1. Liquid chromatographic methods 54 II.1.2. Sample preparation procedures 56 II.1.2.1. Microextraction by packed sorbent assay: a brief overview 57 II.1.3. Validation of bioanalytical methods 59 xiii II.2. Experimental Section - An easy-to-use liquid chromatography assay for the analysis of lamotrigine in rat plasma and brain samples using microextraction by packed sorbent: application to a pharmacokinetic study 61 II.2.1. Introduction 63 II.2.2. Material and methods 64 II.2.2.1. Materials and reagents 64 II.2.2.2. Blank rat matrices 65 II.2.2.3. Stock solutions, calibration standards and quality control samples 65 II.2.2.4. Sample preparation and extraction 66 II.2.2.5. Apparatus and chromatographic conditions 67 II.2.2.6. Method validation 67 II.2.2.7. Method application and pharmacokinetic analysis 68 II.2.3. Results and discussion 69 II.2.3.1. Optimization of chromatographic conditions 69 II.2.3.2. Development and optimization of sample extraction procedure 70 II.2.3.3. Method validation 71 II.2.3.3.1. Selectivity 71 II.2.3.3.2. Calibration curves and LOQ 72 II.2.3.3.3. Precision and accuracy 75 II.2.3.3.4. Recovery 75 II.2.3.3.5. Stability 76 II.2.3.3.6. Method application and pharmacokinetics 76 II.2.4. Conclusion 78 II.3. Experimental Section - Determination of lamotrigine in human plasma and saliva using microextraction by packed sorbent and high performance liquid chromatography–diode array detection: an innovative bioanalytical tool for therapeutic drug monitoring 81 II.3.1. Introduction 83 II.3.2. Material and methods 85 II.3.2.1. Materials and reagents 85 II.3.2.2. Stock solutions, calibration standards and QC samples 85 II.3.2.3. Apparatus and chromatographic conditions 85 II.3.2.4. Sample preparation and extraction 86 II.3.2.5. Method validation 86 II.3.2.6. Clinical application 88 II.3.3. Results and discussion 88 II.3.3.1. Method validation 88 II.3.3.1.1. Selectivity 88 II.3.3.1.2. Calibration curves and LOQ 89 II.3.3.1.3. Precision and accuracy 91 xiv II.3.3.1.4. Recovery 91 II.3.3.1.5. Stability 91 II.3.3.1.6. Clinical application 91 II.3.4. Conclusion 96 CHAPTER III. Effects of Paullinia cupana extract on lamotrigine pharmacokinetics in rats: a herb-drug interaction on the gastrointestinal tract with potential clinical impact 97 III.1. Introduction 99 III.2. Material and Methods 100 III.2.1. Herbal extract, drugs and materials 100 III.2.2. Animals 100 III.2.3. Preparation of herbal extract and lamotrigine solutions 101 III.2.4. Systemic pharmacokinetic studies 101 III.2.5. Plasma-to-brain biodistribution study 102 III.2.6. Liquid chromatography analysis 102 III.2.7. Pharmacokinetic analysis 103 III.2.8. Effects of repeated-dose administration of P. cupana extract on biochemical parameters 103 III.2.9. Effects of repeated-dose administration of P. cupana extract on body weight 103 III.2.10. Statistical analysis 104 III.3. Results 104 III.3.1. Effects of P. cupana extract on LTG pharmacokinetics after co- administration 104 III.3.2. Effects of repeated-dose pretreatment with P. cupana extract on LTG pharmacokinetics 106 III.3.3. Effects of P. cupana extract on the LTG plasma-to-brain biodistribution after co-administration 107 III.3.4. Effects of repeated-dose administration of P. cupana extract on biochemical parameters 109 III.3.5. Effects of repeated-dose administration of P. cupana extract on body weight 110 III.4. Discussion 110 III.5. Conclusion 113 CHAPTER IV. Administration of Garcinia cambogia and lamotrigine: safety evidence from non-clinical pharmacokinetic studies in Wistar rats 115 IV.1. Introduction 117 IV.2. Material and Methods 118 IV.2.1. G. cambogia extract and drugs 118 IV.2.2. Animals 118 IV.2.3. Preparation of G. cambogia extract and LTG solutions 119 IV.2.4. Pharmacokinetic studies 119 xv IV.2.5. LTG quantification 120 IV.2.6. Pharmacokinetic analysis 120 IV.2.7. Effects of repeated-dose administration of G.
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