Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan; Production Department, Odawara Central Factory, Nippon Shinyaku Co., Ltd., 676-1 Kuwahara, Odawara, Kanagawa 250-0861, Japan.
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan; Central Hyogo Area, Hanshin Dispensing Pharmacy, I & H Co., Ltd., 1-18 Ohmasu-cho, Ashiya, Hyogo 659-0066, Japan.
J Pharm Sci. 2024 May;113(5):1209-1219. doi: 10.1016/j.xphs.2023.11.010. Epub 2023 Nov 19.
To clarify the regulation of drug absorption by the enteric nervous system, we investigated how adrenergic agonists (adrenaline (ADR), clonidine (CLO), dobutamine (DOB)) and dibutyryl cAMP (DBcAMP) affected P-glycoprotein (P-gp) function by utilizing isolated rat jejunal sheets and Caco-2 cell monolayers. ADR and CLO significantly decreased the secretory transport (P) of rhodamine-123 and tended to decrease the transport via P-gp (P) and passive transport (P). In contrast, DBcAMP significantly increased and DOB tended to increase P and both tended to increase Pand P. Changes in P-gp expression on brush border membrane by adrenergic agonists and DBcAMP were significantly correlated with P, while P-gp expression was not changed in whole cell homogenates, suggesting that the trafficking of P-gp would be responsible for its functional changes. P was inversely correlated with transmucosal or transepithelial electrical resistance, indicating that adrenergic agonists affected the paracellular permeability. Adrenergic agonists also changed cAMP levels, which were significantly correlated with P. Furthermore, protein kinase A (PKA) or PKC inhibitor significantly decreased P in Caco-2 cell monolayers, suggesting that they would partly contribute to the changes in P-gp activity. In conclusion, adrenergic agonists regulated P-gp function and paracellular permeability, which would be caused via adrenoceptor stimulation.
为了阐明肠神经系统对药物吸收的调节作用，我们研究了肾上腺素（ADR）、可乐定（CLO）、多巴酚丁胺（DOB）等儿茶酚胺激动剂和二丁酰环腺苷酸（DBcAMP）如何通过分离的大鼠空肠片和 Caco-2 细胞单层来影响 P-糖蛋白（P-gp）功能。ADR 和 CLO 显著降低了 rhodamine-123 的分泌转运（P），并倾向于降低通过 P-gp 的转运（P）和被动转运（P）。相比之下，DBcAMP 显著增加，DOB 倾向于增加 P 和 P，两者均倾向于增加 P 和 P。儿茶酚胺激动剂和 DBcAMP 对刷状缘膜 P-gp 表达的改变与 P 显著相关，而在全细胞匀浆中 P-gp 表达没有改变，表明 P-gp 的转运将负责其功能变化。P 与黏膜间或跨上皮电阻呈负相关，表明儿茶酚胺激动剂影响细胞旁通透性。儿茶酚胺激动剂还改变了 cAMP 水平，与 P 显著相关。此外，蛋白激酶 A（PKA）或蛋白激酶 C 抑制剂在 Caco-2 细胞单层中显著降低了 P，表明它们将部分参与 P-gp 活性的变化。总之，儿茶酚胺激动剂调节了 P-gp 功能和细胞旁通透性，这可能是通过肾上腺素受体刺激引起的。
