Species Difference in the Effect of Grapefruit Juice on Intestinal Absorption of Talinolol between Human and Rat
Species Difference in the Effect of Grapefruit Juice on Intestinal Absorption of Talinolol between Human and Rat
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DOI：
10.1124/jpet.109.159756
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发表时间：
2010-01
影响因子：
3.5
通讯作者：
Y. Shirasaka;Erika Kuraoka;H. Spahn‐Langguth;T. Nakanishi;P. Langguth;I. Tamai
中科院分区：
文献类型：
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作者：
Y. Shirasaka;Erika Kuraoka;H. Spahn‐Langguth;T. Nakanishi;P. Langguth;I. Tamai
β1-肾上腺素能受体拮抗剂他林洛尔与葡萄柚汁（GFJ）联合给药可提高其在大鼠体内的生物利用度，而葡萄柚汁可显著降低他林洛尔在人体内的吸收。由于我们最近的研究表明，GFJ对有机阴离子转运多肽（Oatp）和P-gp介导的他林洛尔吸收的抑制作用取决于摄入GFJ中柚皮苷的浓度，因此，这一明显不一致的发现可能是由于柚皮苷对OATP/Oatp和P-gp多药耐药1（MDR 1/Mdr 1）的亲和力在人类和大鼠之间存在种属差异。尽管2000 μM柚皮苷不抑制人MDR 1介导的他林洛尔转运，但在LLC-PK 1细胞和非洲爪蟾卵母细胞系统中，柚皮苷抑制人OATP 1A 2-、大鼠Oatp 1a 5-和大鼠Mdr 1a介导的他林洛尔转运，IC 50值分别为343、12.7和604 μM。由于发现市售GFJ中的柚皮苷浓度约为1200 μM，因此这些结果表明，GFJ可通过抑制OATP 1A 2介导的人体他林洛尔摄取来降低他林洛尔的肠道吸收，而增加他林洛尔吸收主要是通过抑制大鼠中Mdr 1a介导的外排。通过原位闭环方法测量的他林洛尔的大鼠肠渗透性在GFJ存在下确实显著增加，而在6倍稀释的GFJ中观察到显著降低，其中柚皮苷浓度约为200 μM。本研究表明，在人和大鼠之间的他林洛尔的肠吸收的影响的种属差异，可能是由于在两个物种之间的OATP/Oatp和MDR 1/Mdr 1转运蛋白的柚苷的亲和力的差异。
Bioavailability of talinolol, a β1-adrenergic receptor antagonist, was enhanced by coadministration with grapefruit juice (GFJ) in rats, whereas GFJ ingestion markedly reduced the absorption of talinolol in humans. Because our recent study indicated that the inhibitory effect of GFJ on organic anion-transporting polypeptide (Oatp)- and P-gp-mediated talinolol absorption depends on the concentration of naringin in ingested GFJ, the apparent inconsistent findings may be explained by the species difference in the affinity of naringin for OATP/Oatp and P-gp multidrug resistance 1 (MDR1/Mdr1) between humans and rats. Although human MDR1-mediated talinolol transport was not inhibited by 2000 μM naringin, naringin inhibited human OATP1A2-, rat Oatp1a5-, and rat Mdr1a-mediated talinolol transport with IC50 values of 343, 12.7, and 604 μM, respectively, in LLC-PK1 cell and Xenopus laevis oocyte systems. Because the naringin concentration in commercially prepared GFJ was found to be approximately 1200 μM, these results suggested that GFJ would reduce the intestinal absorption of talinolol through inhibition of OATP1A2-mediated talinolol uptake in humans, whereas an increase of talinolol absorption is mainly through inhibition of Mdr1a-mediated efflux in rats. The rat intestinal permeability of talinolol measured by the in situ closed loop method was indeed significantly increased in the presence of GFJ, whereas a significant decrease was observed with 6-fold diluted GFJ, in which the naringin concentration was approximately 200 μM. The present study indicated that the species difference in the effect of GFJ on intestinal absorption of talinolol between humans and rats may be due to differences in the affinity of naringin for OATP/Oatp and MDR1/Mdr1 transporters between the two species.