Quantitative Evaluation of PEPT1 Contribution to Oral Absorption of Cephalexin in Rats
Quantitative Evaluation of PEPT1 Contribution to Oral Absorption of Cephalexin in Rats
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DOI：
10.1007/s11095-008-9703-3
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发表时间：
2009-01-01
影响因子：
3.7
通讯作者：
Kimura, Toshikiro
中科院分区：
文献类型：
--
作者：
Hironaka, Takanori;Itokawa, Shota;Kimura, Toshikiro
PEPT1介导了许多药物的肠道吸收，但其对药物口服吸收的贡献仍存在争议。本研究的目的是定量评价PEPT1的典型底物头孢氨苄在大鼠口服吸收中的作用。采用原位闭环法，以甘氨酰-脯氨酸为竞争性抑制剂，考察了头孢氨辛在5个肠段通过PEPT1和被动扩散的吸收情况。用GI-TRANSPORT-ADM模型预测了头孢氨苄口服后的吸收动力学，头孢氨苄在除回肠下段外的所有肠段的吸收均呈浓度依赖性。PEPT1的本征吸收速率常数范围为0.64~4.07 h(-1)。被动扩散吸收速率常数为0.78~1.24 h(-1)。成功地预测了头孢氨苄的血药浓度-时间分布，并计算出PEPT1对口服吸收的实质性贡献为总吸收的46%至60%。模拟研究表明，即使PEPT1不起作用，头孢氨苄仍有83%的生物利用度。PEPT1对头孢氨苄的口服吸收有很大贡献，约占总吸收的一半。然而，PEPT1的功能可以通过头孢氨苄的被动扩散来补偿。
PEPT1 mediates the intestinal absorption of many drugs, but its contribution to oral absorption of drugs is still controversial. The objective of this study is to quantitatively evaluate the contribution of PEPT1 to oral absorption of cephalexin, a typical substrate for PEPT1, in rats.The absorbability of cephalexin via PEPT1 or passive diffusion was assessed in five intestinal segments by utilizing glycyl-proline as a competitive inhibitor by in-situ closed loop method. Absorption kinetics of cephalexin after oral administration was predicted by GI-Transit-Absorption model.Absorbability of cephalexin was segment-dependent, and concentration-dependent in all the segments except for the lower ileum. Intrinsic absorption rate constant via PEPT1 ranged from 0.64 to 4.07 h(-1). The absorption rate constants via passive diffusion ranged from 0.78 to 1.24 h(-1). Plasma concentration-time profile of cephalexin was successfully predicted and the substantial contribution of PEPT1 to the oral absorption was calculated to be from 46% to 60% of total absorption. Simulation study indicated that 83% bioavailability would be expected for cephalexin even though PEPT1 does not function.PEPT1 substantially contributes to oral absorption of cephalexin, around a half of total absorption. However, the function of PEPT1 can be compensated by passive diffusion for cephalexin.