Prediction of Oral Absorption of Anionic Drugs that are Absorbed by the Monocarboxylic Acid Transport System

一元羧酸转运系统吸收的阴离子药物的口服吸收预测

基本信息

批准号：
11672216
负责人：
ITOH Tomoo
金额：
$ 1.28万
依托单位：
Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672216/
关键词：
Monocarboxylic Acid Transporter Oral Absorption Caco-2 cells Penicillins モノカルボル酸

项目摘要

Transcellular transport of carbenicillin (CBPC) and caridacillin (CIPC) through Caco-2 cell monolayer in the apical to basal direction was measured. CBPC is used pareterally because of poor absorption from the intestine, whereas CIPC is a prodrug of CBPC and is orally administered. Caco-2 cells were cultured on Transwell and the transport was measured at apical pH=6.0 and basal pH=7.4. Permeability of CIPC through Caco-2 cell monolayer was ca. 40-fold greater than that of CBPC, indicating that improved absorption of CIPC is due to much faster transport through the intestinal epithelial cells. Moreover, it was shown that CIPC, not CBPC, was transported by the monocarboxylic acid transport system that is located at the epithelial cells. It is probably true that modification of chemical structure from CBPC to CIPC resulted in much greater affinity to the transport system, which in turn resulted in greater absorption of the prodrug.Transport of cloxacillin (MCIPC), dicloxacillin (MDIPC), phenethicillin (PEPC), phenoxymethylpenicillin (PCV) and propicillin (PPPC) through Caco-2 cell monolayer was measured. Permeability of these drugs ranged from 0.8 to 1.0 x 10^<-6> cm/s. If we assume that these drugs are absorbed only by passive diffusion, extent of absorption after oral administration should be 10-20% of the dose (S.Chong et al., Pharm.Res.13 : 120-123, 1996). However, extent of oral absorption of these drugs in humans is 45-86%, which is much greater than that predicted assuming passive diffusion. The results suggest that a transport system, most probably the monocarboxylic acid transport system, is involved in the absorption of these drugs since these drugs have a carboxylic acid moiety and exist as mono-anion at physiological pH.Moreover, in our previous study, it was demonstrated that these drugs have affinity to the monocarboxylic acid transport system.

测量了羧卞西林 (CBPC) 和卡里西林 (CIPC) 通过 Caco-2 细胞单层从顶端到基底方向的跨细胞转运。 CBPC 由于肠道吸收差而以非胃肠道方式使用，而 CIPC 是 CBPC 的前药并口服给药。 Caco-2细胞在Transwell上培养，并在顶端pH=6.0和基础pH=7.4下测量转运。 CIPC 通过 Caco-2 细胞单层的渗透性约为。比 CBPC 高 40 倍，表明 CIPC 吸收的改善是由于通过肠上皮细胞的运输速度更快。此外，研究表明 CIPC，而不是 CBPC，是由位于上皮细胞的一元羧酸转运系统转运的。化学结构从 CBPC 修改为 CIPC 可能确实会导致与转运系统的亲和力更大，从而导致前药的吸收更大。氯唑西林 (MCIPC)、双氯西林 (MDIPC)、非奈西林 (PEPC) 的转运、苯氧基甲基青霉素 (PCV) 和丙匹西林 (PPPC) 通过 Caco-2 细胞单层进行测量。这些药物的渗透性范围为0.8至1.0×10 ^ -6 cm/s。如果我们假设这些药物仅通过被动扩散吸收，则口服给药后的吸收程度应为剂量的10-20％(S.Chong等人，Pharm.Res.13：120-123，1996)。然而，这些药物在人体中的口服吸收程度为 45-86%，这比假设被动扩散的预测要高得多。结果表明，转运系统（很可能是一元羧酸转运系统）参与了这些药物的吸收，因为这些药物具有羧酸部分并且在生理pH下以单阴离子形式存在。此外，在我们之前的研究中，它已证明这些药物对单羧酸转运系统具有亲和力。