Evaluation of the effect of herbal extracts used in slimming regimens in the kinetic profile of narrow therapeutic range drugs used for cardiovascular pathologies: the amiodarone

摘要

The use of plants for the prevention and treatment of various health diseases has been a practice that comes from the ancient civilizations. However, in recent years has been observed an increase in the use of herbal products. In developed countries is particularly worrying the increasing consumption of herbal weight loss medicines/dietary supplements as alternative or complement to the traditional programs of body weight reduction. In addition, this issue is even more serious because among the general population prevails the notion that herbal preparations are devoid of health risks due to the natural origin of the constituents. Indeed, only a minority recognizes that herbal medicinal products are complex mixtures of phytochemicals, which may be substrates, inhibitors or inducers of the same biological systems that are involved in the biodisposition of conventional drugs, existing, therefore, a high potential for clinically significant pharmacokinetic interactions. Accordingly, considering the close relationship between obesity and cardiovascular diseases, as well as the scarcity of scientific information available about the safety of herbal slimming medicinal products, it is absolutely justified to assess the potential for pharmacokinetic interactions between the most relevant herbal weight loss extracts and high-risk drugs required in multiple cardiovascular diseases such as the case of amiodarone (AM). Thus, from the perspective of protecting public health, it is warranted to characterize the interference of standardized herbal extracts commonly used in weight loss programs (e.g. Fucus vesiculosus, Paullinia cupana, Citrus aurantium and Carica papaya) in the pharmacokinetic profile of AM.This thesis emerged in this context and aimed to carry out the in vivo nonclinical systematic assessment of the potential for occurrence of significant herb-drug interactions between commonly used standardized herbal weight loss extracts and AM, a drug of narrow safety range widely used in clinical practice for the management of cardiovascular diseases. One technique of high performance liquid chromatography (HPLC) with diode-array detection (DAD) was developed and fully validated for adequate quantification of AM and its main metabolite (mono-N-desethylamiodarone) in human plasma in order to provide a useful analytical tool for clinical purposes. A second technique was developed and validated in plasma and heart, liver, kidney, and lung tissue homogenates of rats – species used for in vivo investigations.The herbal extracts that have more pronounced effects on the pharmacokinetics of AM were F. vesiculosus, P. cupana and C. papaya extracts. F. vesiculous extract and P. cupana extract following the co-administration with AM showed a significant reduction of the peak concentration of AM as well as a reduction in the extend of systemic exposure to AM. For the first time were reported herb-drug interactions between F. vesiculosus extract and P. cupana extract with AM, which determined a considerable decrease on AM bioavailability in rats. Therefore, the therapeutic efficacy of AM may be compromised by the concurrent administration of herbal slimming medicines/dietary supplements containing F. vesiculosus or P. cupana.On the other hand, it should be highlighted that the pre-treatment with C. aurantium extract significantly increased the peak concentration of AM, while the extension of systemic exposure was comparable between both groups. At last, in the rats pre-treated with C. papaya extract was observed a significant increase in the systemic exposure of AM. In conclusion, the findings reported along this thesis showed the relevance of screening herb-drug pharmacokinetic interactions. The knowledge of relevant herb-drug interactions is certainly useful to help in the preparation of appropriate herbal monographs such those in course by the Herbal Medicinal Products Committee (HMPC) of the European Medicines Agency (EMA). The availability of this kind of information gathered together in a single and easily accessible document (monograph) may be of great value to promote a more rational and safer use of herbal products, having high importance in terms of protecting the public health.