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- Nonclinical assessment of the potential for herb-drug interactions between herbal extracts present in weight loss supplements and lamotriginePublication . Ventura, Sandra Cristina do Espírito Santo; Alves, Gilberto Lourenço; Ferreira, Amílcar Celta Falcão RamosPlants have been and still continue to be one of the most important sources of active ingredients. Actually, plants are still the backbone of modern pharmacopoeias and remain as a source of new drug candidates. The use of medicinal plants or plant-based medicinal products is also increasing in many developed countries as an alternative and complementary form for the treatment of diseases. Thus, the concomitant use of plants and conventional medications is emerging as a common practice in patients with hypertension, diabetes, epilepsy, depression, and oncological diseases, as well as in people with obesity and being overweight. Recently, obesity and epilepsy have been related as comorbid conditions with a high prevalence, particularly in patients with refractory epilepsy and under polytherapy. Treatment of patients with epilepsy should, therefore, take into account that the presence of comorbid conditions may compromise the efficacy and safety of antiepileptic drugs, which constitute the main therapeutic approach in epilepsy. Lamotrigine (LTG) is a well-tolerated antiepileptic drug widely used in epilepsy; however, it has a narrow therapeutic range and a considerable interindividual variability in its pharmacokinetics. Therefore, the focus of research addressed in this thesis was the nonclinical assessment of the potential for herb-drug interactions between herbal extracts present in weight loss supplements and LTG, using the rat as whole animal model. After optimization and validation of selective, precise and accurate bioanalytical methods for the quantification of LTG in human samples (plasma and saliva) and in rat samples (plasma and brain), the conditions for proceeding with nonclinical studies were met. Therefore, then a number of nonclinical studies were performed in adult male Wistar rats with the main objective of evaluating the effects of standardized extracts of Paullinia cupana (guarana), Garcinia cambogia (malabar tamarind), Citrus aurantium (bitter orange) and Fucus vesiculosus (bladderwrack) on the kinetics of LTG. To this end, at least two independent pharmacokinetic studies were carried out to evaluate the effects of each herbal extract on the pharmacokinetics of LTG; the first study aimed to evaluate the effects after the co-administration of the extract and LTG, and the second one aimed to evaluate the effects of a 14-day pre-treatment period with the extract on the pharmacokinetics of LTG subsequently administered on the 15th day. Globally, the results of the pharmacokinetic studies involving the four herbal extracts pointed out that P. cupana extract is the one that has higher potential to interact with LTG, while G. cambogia, C. aurantium and F. vesiculosus extracts had minor or no effects on LTG pharmacokinetics. The co-administration of P. cupana extract and LTG caused, in particular, a significant decrease in the peak plasma drug concentration (Cmax) and in the extent of systemic exposure to LTG over the first 24 h (AUC0-24). Based on the findings achieved in these nonclinical studies, an important pharmacokinetic interaction between P. cupana extract and LTG was herein described for the first time, which potentially may have clinical impact in patients treated with LTG. Moreover, the repeated administration of the tested herbal extracts during a 14-day period did not have relevant effects on the body weight gain of rats, which raises doubts about their effectiveness in reducing body weight. So, in conclusion, the nonclinical assessment of herb-drug interactions is of utmost importance to anticipate the potential effects of herbal preparations in the pharmacokinetics of narrow therapeutic index drugs like LTG, constituting these data the starting point for further confirmation and investigation of the relevance of these interactions at a clinical level.