权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
14572097
负责人：
ITOH Tomoo
金额：
$ 2.18万
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：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572097/
关键词：
PEPT1 Transporter Oral Absorption penicillins cephems sulfonylureas ACE inhibitors PepT1 Caco-2細胞

项目摘要

It was shown in the present study that oral absorption of some penicillins (cyclacillin, amoxicillin and ampicillin) and cephems (cephradine, cefaclor, cephalexin, ceftibuten, cefixime, cefotiam and cefazolin) can be quantitatively predicted based on in vitro uptake into Caco-2 cells. Uptake of a drug into Caco-2 cells was measured at pH 6.0 in the absence or presence of 30 mM glycyl-sarcosine (Gly-Sar). Initial uptake clearance by PEPT1 (ΔCL_<uptake>) was calculated as the difference between the uptake clearance in the absence of Gly-Sar and that in the presence of 30 mM Gly-Sar. In order to correct for inter-day and/or inter-cell variability, the ΔCL_<uptake> of each drug was then divided by that of cephradine to obtain ΔCL_<uptake>^*. Using the ΔCL_<uptake>^*, the fraction absorbed (Fa) was calculated according to the equation derived from the complete radial mixing (CRM) model. Good correlation was observed between the observed and predicted Fa values.Oral absorption of these drugs can also be predicted based on in vitro uptake into PEPT1-expressing cells (HeLa-PEPT1 cells). Fa was predicted in the same manner as described above except that ΔCL_<uptake> was calculated as the difference between the uptake into HeLa-PEPT1 cells and that into mock cells.In HeLa-PEPT1 cells, however, it was demonstrated that captopril was not transported by PEPT1. Captopril is an ACE inhibitor that has been believed to be absorbed via PEPT1. When Caco-2 cells are used in the present prediction, other transporters may be involved for uptake of drugs, which may result in over-estimate of oral absorption. We expect that the present prediction method with HeLa-PEPT1 cells will be improved for screening a large number of drug candidates for PEPT1-mediated absorption.

本研究表明，可以根据Caco-2细胞的体外摄取定量预测某些青霉素类（环拉西林、阿莫西林和氨苄西林）和头孢烯类（头孢拉定、头孢克洛、头孢氨苄、头孢布烯、头孢克肟、头孢替安和头孢唑林）的口服吸收。在不存在或存在30 mM甘氨酰-肌氨酸（Gly-Sar）的情况下，在pH 6.0下测量药物对Caco-2细胞的摄取。PEPT 1的初始摄取清除率（ΔCL_<uptake>）计算为不存在Gly-Sar和存在30 mM Gly-Sar时的摄取清除率之间的差异。为了校正日间和/或细胞间变异性，<uptake>然后将每种药物的ΔCL_除以头孢拉定的Δ CL_，以获得ΔCL_<uptake>^*。根据<uptake>完全径向混合（CRM）模型导出的方程，使用ΔCL_（1 *）计算吸收分数（Fa）。观察到的Fa值与预测值之间具有良好的相关性。这些药物的口服吸收也可以基于PEPT 1表达细胞（HeLa-PEPT 1细胞）的体外摄取来预测。以与上述相同的方式预测Fa，不同之处在于ΔCL_计算<uptake>为HeLa-PEPT 1细胞和模拟细胞的摄取之间的差异。Captopril是一种ACE抑制剂，被认为通过PEPT 1吸收。当在本预测中使用Caco-2细胞时，其他转运蛋白可能参与药物摄取，这可能导致高估口服吸收。我们希望，目前的预测方法与HeLa-PEPT 1细胞将得到改善，筛选大量的候选药物PEPT 1介导的吸收。