Herb-drug interaction: effect of Fucus vesiculosus extract on the bioavailability and disposition of amiodarone in rats

M Rodrigues1,2, M Matias3, C Canário3, J Abrantes1,2, A Ferreira3, G Alves2,3, A Falcão1,2. 1Laboratory of Pharmacology, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal, 2CNC – Centre for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal, 3CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal

Fucus vesiculosus is a seaweed claimed to be useful for obesity management. Considering the close relationship between obesity and cardiovascular diseases, as well as the scarcity of available scientific information about the safety of herbal slimming medicines/supplements, it is urgent to assess the potential for pharmacokinetic interactions between the most relevant herbal weight loss extracts and high-risk drugs frequently used in cardiovascular disorders. Thus, the present in vivo study was designed to investigate the effect of a standardized Fucus vesiculosus extract on the bioavailability of amiodarone, a narrow therapeutic index drug, in Wistar rats.

On the day before dosing, a lateral tail vein of each rat was cannulated, under anaesthesia [ketamine (90 mg/kg)/xylazine (10 mg/kg), i.p. injection], by insertion of an indwelling cannula used for serial blood sampling. In the following day, adult male Wistar rats (n=6) were simultaneously co-administered with a single-dose of Fucus vesiculosus (575 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.) by gavage. Rats of the control group were administered with the corresponding volume of vehicle of the extract and amiodarone (50 mg/kg, p.o.). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 h after dosing; the last blood sample (24 h) was taken by a terminal procedure (decapitation and exsanguination under anaesthesia). Furthermore, to investigate some aspects related to the biodisposition of amiodarone and mono-N-desethylamiodarone (major metabolite of amiodarone) in rats, several tissues (heart, liver, kidneys and lungs) were also harvested at 24 h. Then, plasma and tissue concentrations of amiodarone and mono-N-desethylamiodarone were measured by HPLC-DAD.

After examination of the obtained plasma pharmacokinetic data, estimated by non-compartimental analysis, it deserves to be highlighted the significant decrease in the peak plasma concentration of amiodarone in the group of rats treated with Fucus vesiculosus extract versus the control group (0.615 ± 0.060 µg/mL vs. 1.378 ± 0.179 µg/mL, p<0.005) ); in addition, a considerable reduction of the systemic exposure to amiodarone (as assessed by AUC0-t) was also observed in the experimental group comparatively to the control group (8.995 ± 0.725 μg.h/mL vs. 12.774 ± 0.688 μg.h/mL, p<0.005). Moreover, amiodarone and mono-N-desethylamiodarone were found in concentrations considerably lower in plasma than in tissues, supporting their great plasma/tissue distribution; these differences were absolutely remarkable for the lung tissue-to-plasma ratio.

Our results showed, for the first time, an herb-drug interaction between Fucus vesiculosus extract and amiodarone, which determined a considerable decrease on the bioavailability/systemic exposure of amiodarone in rats. Therefore, the therapeutic efficacy of amiodarone may be compromised by the concurrent administration of herbal slimming medicines/supplements containing Fucus vesiculosus.

Acknowledgements : Fundação para a Ciência e a Tecnologia (SFRH/BD/61901/2009; SFRH/BPD/46826/2008), Portugal.