Mori N, Shimomukai Y, Yokooji T, Ishiguro M, Kamio Y, Murakami T
Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan.
Pharmazie. 2011 Mar;66(3):207-11.
The characteristics of intestinal absorption of mizoribine and cephalexin, that are mediated by concentrative nucleoside transporters (CNTs) and PEPT1, respectively, was examined in lipopolysaccharide (LPS)-treated rats. LPS treatment is known to modify the expression of some transporters and induce cholestasis. At 24 h after the LPS treatment, averaged concentrations of IL-6 and total bile acids in plasma were 15-fold and 2-fold that in untreated control rats, respectively, and bile flow rate decreased by 40% of control, indicating the induction of inflammatory and cholestatic states. The oral bioavailability, estimated by urinary excretion percentage of unchanged form, of mizoribine in LPS-treated rats was 1.5-fold higher than that in control rats, whereas the bioavailability of cephalexin remained unchanged. When mizoribine and cephalexin were administered into in-situ jejunum loops, there were no differences in the absorption rates between control and LPS-treated rats. These results indicated that the functional expression of CNT1, CNT2, and PEPT1 were not modulated by LPS treatment. When mizoribine (a CNT1/CNT2 substrate) and gemcitabin (a CNT1 substrate) were administered as a solution dissolved in bile into the intestinal loop, their absorption rates decreased significantly. In contrast, the absorption rate of ribavirin (a CNT2 substrate) remained unchanged. In conclusion, LPS treatment exerted no significant effect on the expression of CNT1 and CNT2 in the intestine. Bile was found to suppress the CNT1-mediated intestinal absorption of mizoribine and gemcitabin. The increased oral bioavailability of mizoribine in LPS-treated rats could be ascribed to the less amount of bile or bile acids in the intestine under cholestatic state of rats.
在脂多糖（LPS）处理的大鼠中，研究了分别由集中核苷转运体（CNTs）和肽转运体1（PEPT1）介导的咪唑立宾和头孢氨苄的肠道吸收特性。已知LPS处理会改变某些转运体的表达并诱导胆汁淤积。LPS处理后24小时，血浆中白细胞介素-6（IL-6）和总胆汁酸的平均浓度分别是未处理对照大鼠的15倍和2倍，胆汁流速降低至对照的40%，表明诱导了炎症和胆汁淤积状态。通过未变化形式的尿排泄百分比估算，LPS处理大鼠中咪唑立宾的口服生物利用度比对照大鼠高1.5倍，而头孢氨苄的生物利用度保持不变。当将咪唑立宾和头孢氨苄注入原位空肠肠袢时，对照大鼠和LPS处理大鼠之间的吸收率没有差异。这些结果表明，LPS处理未调节CNT1、CNT2和PEPT1的功能表达。当将咪唑立宾（一种CNT1/CNT2底物）和吉西他滨（一种CNT1底物）以溶解于胆汁的溶液形式注入肠袢时，它们的吸收率显著降低。相比之下，利巴韦林（一种CNT2底物）的吸收率保持不变。总之，LPS处理对肠道中CNT1和CNT2的表达没有显著影响。发现胆汁可抑制CNT1介导的咪唑立宾和吉西他滨的肠道吸收。LPS处理大鼠中咪唑立宾口服生物利用度的增加可能归因于大鼠胆汁淤积状态下肠道中胆汁或胆汁酸量的减少。
