Takeda Fuyo, Oda Masako, Terasaki Masaru, Kubota Atsuhito, Asada Keita, Ichimura Yuichi, Kojima Hiroyuki, Saitoh Hiroshi
Department of Pharmaceutics, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
Department of Health and Environmental Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan.
Drug Metab Pharmacokinet. 2021 Oct;40:100411. doi: 10.1016/j.dmpk.2021.100411. Epub 2021 Jun 15.
The expression of transporters on the apical and basal membranes of renal tubular cells is modulated under acute kidney injury (AKI). However, little is known about alterations in non-renal transporters in the tissues other than the kidney under AKI situation. This study aimed to assess the modulation of organic anion transporting polypeptide (Oatp) 1a2 and Oatp2b1 expression/function in the small intestine of rats with drug-induced AKI. AKI was induced by intraperitoneal administration of cisplatin at a dose of 5 mg/kg. On day 3 after cisplatin administration, morphological changes in the small intestine, Oatp1a2 and Oatp2b1 expression, and absorption of pravastatin and theophylline were evaluated. Non-negligible atrophy was observed in the jejunum and ileum of the AKI rats. However, the absorption of theophylline was not affected. While intestinal Oatp2b1 expression was markedly decreased in the AKI rats, no alteration was observed in Oatp1a2 expression. The plasma levels of pravastatin after intraluminal administration declined significantly in the AKI rats. However, no such decline was observed after intravenous administration. This study suggested that the responses of intestinal Oatps to experimentally induced AKI was not unidirectional and that pravastatin absorption was governed more potently by Oatp2b1 than by Oatp1a2 in the rat intestine.
在急性肾损伤(AKI)情况下,肾小管细胞顶端和基底膜上转运蛋白的表达受到调节。然而,对于AKI情况下肾脏以外组织中非肾转运蛋白的变化知之甚少。本研究旨在评估药物诱导的AKI大鼠小肠中有机阴离子转运多肽(Oatp)1a2和Oatp2b1表达/功能的调节情况。通过腹腔注射5mg/kg顺铂诱导AKI。在给予顺铂后第3天,评估小肠的形态变化、Oatp1a2和Oatp2b1的表达以及普伐他汀和茶碱的吸收情况。在AKI大鼠的空肠和回肠中观察到了不可忽视的萎缩。然而,茶碱的吸收未受影响。虽然AKI大鼠小肠中Oatp2b1的表达明显降低,但未观察到Oatp1a2表达的改变。腔内给药后,AKI大鼠普伐他汀的血浆水平显著下降。然而,静脉给药后未观察到这种下降。本研究表明,小肠Oatps对实验诱导的AKI的反应并非单向,并且在大鼠小肠中,普伐他汀的吸收受Oatp2b1的影响比受Oatp1a2的影响更大。