UCL SCHOOL OF PHARMACY Evaluation of herb-drug interactions in Nigeria with a focus on medicinal plants used in diabetes management By: Ezuruike F. Udoamaka A THESIS SUBMITTED IN FULFILMENT OF THE REQUIREMENTS FOR THE AWARD OF THE DEGREE OF DOCTOR OF PHILOSOPHY 2015 1 DECLARATION This thesis describes research conducted in the School of Pharmacy, University College London between October 2010 and January 2015 under the supervision of Dr. Jose M. Prieto-Garcia. It is being submitted for the degree of Doctor of philosophy (PhD), University College London and has not been submitted before for any degree or examination in any other University. I confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signed: ..........................................this day................................................2015 2 ABSTRACT Studies have shown an increasing use of herbal medicines alongside conventional drugs by patients in their disease management especially for chronic diseases, with the attendant risks of herb-drug interactions. In order to forestall this, adequate information about the pharmacological and toxicological profile of herbal medicines and how these would in turn affect the bioavailability of the co-administered drug is required. To evaluate potential herb-drug interactions that could occur in diabetes management in Nigeria- (a) An assessment of available data on the pharmacological and toxicological effects of plants used in diabetes management was conducted as a means of mapping those with identified potential risks for herb-drug interactions; (b) A field work study was carried out in different localities in Nigeria to identify potential pharmacokinetic interactions based on the prescription drugs and herbal medicines co-administered by diabetic patients; and (c) Experimental analysis of plant samples collected during the field work was done to assess their effects on known cell detoxification mechanisms and pharmacokinetic parameters. The results of the research have confirmed the continued use of a wide range of medicinal plants in diabetes management, many of which have not been thoroughly investigated. In addition, 50% of diabetic patients visiting healthcare facilities in Nigeria routinely manage their diabetes or existing co-morbidities with herbal medicines alongside prescription drugs. Even more worrying is the frequent use of unlabeled herbal preparations which would constitute a huge challenge in the proper identification of herb-drug interactions when they occur. Based on previously available data and the experimental results of this research, a number of these herbal medicines have been identified as having overlapping interactions with prescription drugs. There is therefore a need for better regulation of herbal medicine use alongside pharmacovigilance monitoring in Nigeria in order to forestall the occurrence of clinically relevant untoward herb-drug interactions. 3 GRAPHICAL ABSTRACT • Criticasl assessment of the pharmacological and toxicological data on medicinal plants used in Nigeria for the management of diabetes. • Potential implications of the data in Data Mining herb-drug interactions. Work . •Field-work studies on the traditional management of diabetes in Nigeria. •Survey on clinical management of diabetes in Nigeria. •Survey on concurrent use of herbs and Field Work drugs by diabetic patients in Nigeria. • Effects of selected Nigerian medicinal plants on Phase II metabolism. • Effects of selected Nigerian medicinal plants on Radical scavenging Experimental • Effects of selected Nigerian medicinal Work plants on glibenclamide transport 4 DEDICATION To dad, for motivating me to start the PhD; and Nedu for being the backbone on which the work was done. I love you both. 5 ACKNOWLEDGEMENTS My first and utmost gratitude for the success of this PhD goes to God Almighty for making this dream a reality. I wish to express my sincere gratitude to my supervisor, Dr Jose Prieto for his unwavering support throughout the course of this PhD. His willingness to go the extra mile for his students is very much appreciated. I would also like to thank Prof Michael Heinrich and Prof Simon Gibbons for their wisdom, advice and support both academically and otherwise during these past four years. The support of the different members of staff and colleagues at SOP who contributed to making my work a lot easier isn’t unrecognised. Thank you for making the completion of this PhD a reality. I would like to appreciate my fellow PhD students in Rooms 201, 203 and 208. Your friendship made student life a pleasurable one. I wouldn’t have wished for better companions to study with. I want to sincerely thank Tony, Ines, Hannah, Johanna, Fon, Blessing, Andre and Jawharah for their willingness to come to my aid in difficult times; and Fionn for coming along at a very critical time. The results of the fieldwork wouldn’t have been possible without the various respondents who were willing to give up some of their valuable time to answer my questions as well as other people who facilitated things in one way or the other especially Dr Emmanuel Osuala, Fr Anselm Adodo of Pax Herbal and Mallam Muazu. I am very grateful for all the help. I cannot fail to remember the support of various staff and members of the Goodenough community. It is truly a home away from home and so many people too numerous to mention were contributory to the success of this PhD for which I’m really grateful. Special thanks to the Schmenner, Peralta, Ordonez and Gamble families and to Seun and Bk for your friendship as well as for co-opting mama as one of your own at critical moments. My family both home and abroad have been of immeasurable emotional, spiritual and financial support at every step of the way. This PhD thesis is written in your honour. Finally, I would like to acknowledge the Commonwealth scholarship commission for funding this PhD, particularly for the additional support provided to scholars coming with their families. 6 TABLE OF CONTENTS 1 GENERAL INTRODUCTION .................................................................... 15 1.1 HISTORY OF THE USE OF HERBAL MEDICINE AND THE INCIDENCE OF HERB-DRUG INTERACTIONS ................................................................................................. 16 1.2 EXPERIMENTAL TARGETS FOR EVALUATING PHARMACOKINETIC HERB- DRUG INTERACTIONS ............................................................................................................. 20 1.2.1 Herb-Drug interactions involving P-glycoprotein ............................................................ 21 1.2.2 Herb-drug interactions involving Cytochrome P450 enzymes.......................................... 24 1.2.3 Herb-drug interactions involving Phase II metabolising enzymes .................................... 26 1.3 PREDICTION OF HERB DRUG INTERACTIONS AND ITS IMPLICATION IN DISEASE MANAGEMENT ......................................................................................................... 27 1.4 DIABETES MANAGEMENT IN NIGERIA AND THE RISK OF HERB-DRUG INTERACTIONS ......................................................................................................................... 30 1.4.1 Overview of Diabetes ..................................................................................................... 30 1.4.2 Current Therapeutic Options in the Management of Type-2 Diabetes .............................. 31 1.4.3 Clinical Management of Diabetes in Nigeria ................................................................... 34 1.4.4 Potential Risks of Herb-Drug Interactions amongst Diabetic Patients .............................. 36 1.5 AIM OF THESIS ............................................................................................................. 42 1.5.1 Research strategy ........................................................................................................... 42 2 CRITICAL ASSESSMENT OF PHARMACOLOGICAL AND TOXICOLOGICAL DATA FOR MEDICINAL PLANTS USED IN DIABETES MANAGEMENT IN NIGERIA ...................................................... 43 2.1 INTRODUCTION ........................................................................................................... 44 2.2 METHOD ......................................................................................................................... 44 2.3 RESULTS AND DISCUSSION........................................................................................ 45 2.3.1 Assessment of the Preclinical Pharmacological Evidence ................................................ 46 2.3.1.1 In vivo hypoglycaemic activity .............................................................................. 46 2.3.1.2 In vitro pharmacological evidence .......................................................................... 47 2.3.1.3 Bioactive compounds ............................................................................................. 49 2.3.1.3.1 Nitrogen containing compounds ........................................................................ 50 2.3.1.3.2 Terpenes ........................................................................................................... 51 7 2.3.1.3.3 Phenolic compounds ......................................................................................... 52 2.3.1.3.4 Hydroxylated compounds including sugars ....................................................... 56 2.3.2 Assessment