Intestinal transport of β-lactam antibiotics:: Analysis of the affinity at the H+/peptide symporter (PEPT1), the uptake into Caco-2 cell monolayers and the transepithelial flux
Intestinal transport of β-lactam antibiotics:: Analysis of the affinity at the H+/peptide symporter (PEPT1), the uptake into Caco-2 cell monolayers and the transepithelial flux
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DOI：
10.1023/a:1018814627484
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发表时间：
1999-01-01
影响因子：
3.7
通讯作者：
Neubert, R
中科院分区：
文献类型：
--
作者：
Bretschneider, B;Brandsch, M;Neubert, R
目的.本研究以β-内酰胺类抗生素为研究对象，探讨了细胞转运参数与其生物利用度的相关性。通过测定23种β-内酰胺类抗生素抑制甘氨酰肌氨酸进入Caco-2细胞的能力、其进入细胞的能力以及其穿过细胞单层的总通量来表征其转运。头孢布烯和环拉西林被PEPT 1识别，其亲和常数与天然二肽的亲和常数相当（Ki分别为0.3和0.5 mM）。头孢羟氨苄、头孢孟多、头孢拉定、头孢克洛、头孢呋辛酯、头孢克肟、头孢菌素、头孢氨苄和氨苄青霉素也与PEPT 1相互作用（Ki = 7-14 mM）。相反，头孢匹林、头孢地嗪、头孢呋辛、头孢美唑、头孢他啶、苄青霉素、头孢曲松、头孢匹罗、头孢噻肟、头孢吡肟、头孢噻啶和头孢磺啶对转运系统没有亲和力（Ki> 20 mM）。这些β-内酰胺抗生素的细胞摄取和跨上皮通量最高，对[C-14]Gly-Sar转运的抑制作用最强（p < 0.0001）。头孢呋辛酯和头孢菌素类药物。β-内酰胺类抗生素的口服生物利用度主要取决于其与PEPT 1的亲和力。相对于Gly-Sar摄取，需要14 mM的阈值Ki值。
Purpose. This study on the intestinal transport of p-lactam antibiotics was undertaken to investigate the correlation between cellular transport parameters and the bioavailability.Methods. Transport of 23 beta-lactam antibiotics was characterized by measuring their ability to inhibit the uptake of glycylsarcosine into Caco-2 cells, their uptake into the cells and their total flux across the cell monolayers.Results. Ceftibuten and cyclacillin were recognized by PEPT1 with affinity constants comparable to those of natural dipeptides (K-i = 0.3 and 0.5 mM, respectively). Cefadroxil, cefamandole, cephradine, cefaclor, cefuroxime-axetil, cefixime, cephalotin, cephalexin and ampicillin also interacted with PEPT1 (K-i = 7-14 mM). In contrast, cefapirin, cefodizime, cefuroxime, cefmetazole, ceftazidime, benzylpenicillin, ceftriaxone, cefpirome, cefotaxime, cefepime, cephaloridine and cefsulodin displayed no affinity to the transport system (K-i > 20 mM). The uptake into the cells and the transepithelial flux was highest for those beta-lactam antibiotics, which showed the strongest inhibition of [C-14]Gly-Sar transport (p < 0.0001). Exceptions were cefuroximaxetil and cephalotin.Conclusions. The probability of oral bioavailability for beta-lactam antibiotics is mainly determined by their affinity to PEPT1. A threshold K-i value of 14 mM with respect to Gly-Sar uptake is required.