Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice
Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice
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DOI：
10.1038/sj.clpt.6100104
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发表时间：
2007-04-01
影响因子：
6.7
通讯作者：
Kim, R. B.
中科院分区：
文献类型：
--
作者：
Bailey, D. G.;Dresser, G. K.;Kim, R. B.
我们先前研究表明，葡萄柚汁和橙子汁在体外可抑制人肠道有机阴离子转运多肽（OATP）1A 2，并在临床上降低口服非索非那定的生物利用度。在体外进行了葡萄柚（柚皮苷）和橙子（橙皮苷）中黄酮类化合物对OATP 1A 2转运的抑制。在临床上进行了两项随机、交叉、药代动力学研究。在一项研究中，将120 mg非索非那定与300 ml葡萄柚汁、相同果汁浓度（1，200 μ M）的柚皮苷水溶液或水一起摄入。在另一项研究中，非索非那定与葡萄柚汁一起给药，与含有已知的肠CYP 3A 4临床抑制剂但相对较低的柚皮苷浓度（34 μ M）的果汁颗粒部分的水混悬液一起给药或在给药前2小时给药，或与水一起给药。柚苷和橙皮苷的半最大抑制分别为3.6和2.7 μ M。非索非那定在葡萄柚汁和柚皮苷溶液中的血药浓度-时间曲线下面积（AUC）分别为水的55%（P < 0.001）和75%（P < 0.05）。葡萄柚汁和颗粒组分的非索非那定AUC分别为水的57%（P < 0.001）、96%（不显著（NS））和97%（NS）。两项研究中受试个体（n = 9/12）的非索非那定AUC与水（r（2）= 0.85，P <0.001）和与葡萄柚汁（r（2）= 0.72，P < 0.01）的降低程度具有高度重现性。柚皮苷很可能直接抑制肠OATP 1A 2，从而降低口服非索非那定的生物利用度。可能不涉及肠道CYP 3A 4的失活。柚苷似乎具有足够的安全性、特异性和灵敏度，可作为临床OATP 1A 2抑制剂探针。固有的OATP 1A 2活性可能受到遗传因素的影响。这似乎是第一个单一的饮食成分临床调节药物转运的报告。
We showed previously that grapefruit and orange juices inhibited human enteric organic anion-transporting polypeptide (OATP) 1A2 in vitro and lowered oral fexofenadine bioavailability clinically. Inhibition of OATP1A2 transport by flavonoids in grapefruit (naringin) and orange (hesperidin) was conducted in vitro. Two randomized, crossover, pharmacokinetic studies were performed clinically. In one study, 120 mg of fexofenadine was ingested with 300 ml grapefruit juice, an aqueous solution of naringin at the same juice concentration (1,200 mu M), or water. In the other study, fexofenadine was administered with grapefruit juice, with or 2 h before aqueous suspension of the particulate fraction of juice containing known clinical inhibitors of enteric CYP3A4, but relatively low naringin concentration ( 34 mu M), or with water. Naringin and hesperidin's half-maximal inhibitions were 3.6 and 2.7 mu M, respectively. Fexofenadine area under the plasma drug concentration-time curves (AUCs) with grapefruit juice and naringin solution were 55% (P < 0.001) and 75% (P < 0.05) of that with water, respectively. Fexofenadine AUCs with grapefruit juice and particulate fractions were 57% (P < 0.001), 96% (not significant (NS)), and 97% (NS) of that with water, respectively. Individuals tested in both studies (n = 9 of 12) had highly reproducible fexofenadine AUC with water (r(2) = 0.85, Po0.001) and extent of reduction of it with grapefruit juice (r(2) = 0.72, P < 0.01). Naringin most probably directly inhibited enteric OATP1A2 to decrease oral fexofenadine bioavailability. Inactivation of enteric CYP3A4 was probably not involved. Naringin appears to have sufficient safety, specificity, and sensitivity to be a clinical OATP1A2 inhibitor probe. Inherent OATP1A2 activity may be influenced by genetic factors. This appears to be the first report of a single dietary constituent clinically modulating drug transport.