Uesawa Y, Abe M, Fukuda E, Baba M, Okada Y, Mohri K
Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan.
Pharmazie. 2011 Jul;66(7):525-8.
Grapefruit juice (GFJ) is known to affect the pharmacokinetics of a variety of drugs administered concomitantly and this is due to inhibition of intestinal CYP3A, a barrier protein for drug absorption. Some compounds such as furanocoumarin derivatives have been reported as inhibitors of the enzyme. On the other hand, inhibitory potentials of GFJ on CYP3A-oxidation activities differ widely between brands of juices. Information on the percentage contributed by ingredients in GFJ is also limited. Therefore, construction of prediction models for the CYP3A inhibitory potentials of GFJ brands was attempted by using concentrations of ingredients in GFJ. Concentrations of bergaptol, bergamottin, 6', 7'-dihydroxybergamottin, naringin, and naringenin in 23 kinds of GFJ were determined with high-performance liquid chromatography (HPLC). Furthermore, inhibitory effects on CYP3A activity were measured based on the initial rate for testosterone 6beta-hydroxylation in the presence of each GFJ. Results of multi-regression analyses between the ingredients and the enzymatic inhibitory effects revealed that concentrations of bergamottin, 6',7'-dihydroxybergamottin, and naringin were significant variables for CYP3A inhibition of GFJ. According to the standard partial regression coefficient for each explanatory variable, bergamottin and 6',7'-dihydroxybergamottin are the most important factors for inhibition. The multiple correlation coefficient (R) and the multiple correlation coefficient with leave-one-out cross validation (Q) of the model equation were 0.94 and 0.91, respectively. These results suggest that the concentrations of ingredients can explain most variances of inhibitory effects among brands. This model may be a useful method for the prediction of the GFJ interaction potential.
已知葡萄柚汁（GFJ）会影响多种同时服用药物的药代动力学，这是由于其抑制了肠道细胞色素P450 3A（CYP3A），而CYP3A是药物吸收的屏障蛋白。一些化合物如呋喃香豆素衍生物已被报道为该酶的抑制剂。另一方面，不同品牌葡萄柚汁对CYP3A氧化活性的抑制潜力差异很大。关于葡萄柚汁中成分所占百分比的信息也很有限。因此，尝试通过使用葡萄柚汁中成分的浓度来构建葡萄柚汁品牌对CYP3A抑制潜力的预测模型。采用高效液相色谱法（HPLC）测定了23种葡萄柚汁中佛手柑醇、香豆素、6'，7'-二羟基香豆素、柚皮苷和柚皮素的浓度。此外，基于在每种葡萄柚汁存在下睾酮6β-羟基化的初始速率，测量了对CYP3A活性的抑制作用。成分与酶抑制作用之间的多元回归分析结果表明，香豆素、6'，7'-二羟基香豆素和柚皮苷的浓度是葡萄柚汁抑制CYP3A的显著变量。根据每个解释变量的标准偏回归系数，香豆素和6'，7'-二羟基香豆素是抑制作用的最重要因素。模型方程的多重相关系数（R）和留一法交叉验证的多重相关系数（Q）分别为0.94和0.91。这些结果表明，成分浓度可以解释不同品牌之间抑制作用的大部分差异。该模型可能是预测葡萄柚汁相互作用潜力的一种有用方法。
