Brandin Helena, Myrberg Olle, Rundlöf Torgny, Arvidsson Ann-Kristin, Brenning Gunilla
Laboratory Department, Medical Products Agency, Box 26, SE, 751 03, Uppsala, Sweden.
Eur J Clin Pharmacol. 2007 Jun;63(6):565-70. doi: 10.1007/s00228-007-0289-1. Epub 2007 Mar 20.
Grapefruit seed extract (GSE) is promoted as a natural product with antibacterial and antiviral properties. The aim of this study was to investigate the composition of some commercially available GSE products and evaluate their effect in vitro on two cytochrome P450 enzymes, CYP2C9 and CYP3A4.
A couple on lifelong treatment with warfarin and continuous regular follow-ups took some drops of a GSE product for 3 days. The female patient experienced a minor subcutaneous haematoma 3 days later, and her international normalised ratio (INR) value was 7.9. This was reported to the Swedish Medical Products Agency (MPA) as a spontaneous post-marketing report concerning adverse drug reactions/interactions. The composition of the GSE products was determined by proton and carbon-13 nuclear magnetic resonance spectroscopy (NMR). The inhibitory effect of the GSE products on the cytochrome P450 enzymes was tested in an in vitro baculosome assay.
The NMR analysis showed that all three investigated GSE products contained the synthetic preservative benzethonium chloride (BTC) in addition to glycerol and water. No authentic GSE extract was found in any of the three GSE products analysed. Furthermore, BTC was found to be a potent inhibitor of CYP3A4 and CYP2C9 activity in vitro.
Our results suggest that BTC in the GSE products is responsible for the increase in the INR value in a patient on warfarin treatment.
葡萄柚籽提取物（GSE）被宣传为具有抗菌和抗病毒特性的天然产品。本研究的目的是调查一些市售GSE产品的成分，并评估它们在体外对两种细胞色素P450酶CYP2C9和CYP3A4的作用。
一对接受华法林终身治疗并持续定期随访的夫妇服用了几滴GSE产品，持续3天。3天后，女性患者出现轻微皮下血肿，其国际标准化比值（INR）为7.9。这作为一份关于药物不良反应/相互作用的自发上市后报告上报给了瑞典药品管理局（MPA）。通过质子和碳-13核磁共振光谱（NMR）测定GSE产品的成分。在体外杆状脂质体试验中测试GSE产品对细胞色素P450酶的抑制作用。
NMR分析表明，所有三种研究的GSE产品除甘油和水外，还含有合成防腐剂苄索氯铵（BTC）。在所分析的三种GSE产品中均未发现真正的GSE提取物。此外，发现BTC在体外是CYP3A4和CYP2C9活性的有效抑制剂。
我们的结果表明，GSE产品中的BTC是导致接受华法林治疗的患者INR值升高的原因。
