Effect of excessive serotonin on pharmacokinetics of cephalexin after oral administration: Studies with serotonin-excessive model rats
Effect of excessive serotonin on pharmacokinetics of cephalexin after oral administration: Studies with serotonin-excessive model rats
复制标题
血清素过量对口服头孢氨苄药代动力学的影响：血清素过量模型大鼠的研究
DOI：
10.1007/s11095-022-03325-8
复制
发表时间：
2022
影响因子：
3.7
通讯作者：
Kazutaka Higaki
中科院分区：
文献类型：
--
作者：
Shun Nakashima;Takeharu Iwamoto;Masashi Takanashi;Ken-ichi Ogawara;Masato Maruyama;Kazutaka Higaki
目的5-羟色胺(5-HT)对胃肠功能有重要作用，但其在药物吸收中的作用尚不清楚。方法采用5-羟色胺和5-羟色胺代谢抑制剂Clorgyline多次给药的方法制备5-羟色胺过量大鼠模型，研究其药代动力学、吸收行为和肠道通透性。结果5-羟色胺过量大鼠脑、血浆和小肠中5-羟色胺水平较高，口服生物利用度显著提高。肠粘膜被动扩散的CEX转运显著增加，而PEPT1转运显著减少，尤其是在空肠段，这与肠上皮细胞刷状缘膜PEPT1表达的减少有关。由于在5-羟色胺过量的大鼠中没有观察到安替比林通透性的变化和FITC葡聚糖-4通透性的显著增加，CEX通透性的增加可能归因于紧密连接的开放，而跨粘膜电阻的显著降低支持了CEX通透性的增加。结论5-羟色胺过量可提高CEX的口服生物利用度，其机制可能与CEX经PEPT1转运减少，但通过被动扩散途径通过肠粘膜通透性增加有关。
PurposeSerotonin (5-HT) is important for gastrointestinal functions, but its role in drug absorption remains to be clarified. Therefore, the pharmacokinetics and oral absorption of cephalexin (CEX) were examined under 5-HT-excessive condition to understand the role of 5-HT.Methods5-HT-excessive rats were prepared by multiple intraperitoneal dosing of 5-HT and clorgyline, an inhibitor for 5-HT metabolism, and utilized to examine the pharmacokinetics, absorption behavior and the intestinal permeability for CEX.ResultsHigher levels of 5-HT in brain, plasma and small intestines were recognized in 5-HT-excessive rats, where the oral bioavailability of CEX was significantly enhanced. The intestinal mucosal transport via passive diffusion of CEX was significantly increased, while its transport via PEPT1 was markedly decreased specifically in the jejunal segment, which was supported by the decrease in PEPT1 expression on brush border membrane (BBM) of intestinal epithelial cells. Since no change in antipyrine permeability and significant increase in FITC dextran-4 permeability were observed in 5-HT-excessive rats, the enhanced permeability for CEX would be attributed to the opening of tight junction, which was supported by the significant decrease in transmucosal electrical resistance. In 5-HT-excessive rats, furthermore, total body clearance of CEX tended to be larger and the decrease in PEPT2 expression on BBM in kidneys was suggested to be one of the reasons for it.Conclusions5-HT-excessive condition enhanced the oral bioavailability of CEX in rats, which would be attributed to the enhanced permeability across the intestinal mucosa via passive diffusion through the paracellular route even though the transport via PEPT1 was decreased.