Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-5633, USA.
Pharm Res. 2013 Apr;30(4):1017-25. doi: 10.1007/s11095-012-0937-8. Epub 2012 Dec 7.
To determine the contribution of intestinal PepT1 on the permeability and oral absorption of the β-lactam antibiotic drug cefadroxil.
The effective permeability (P eff ) of cefadroxil was evaluated in wild-type and PepT1 knockout mice following in situ single-pass intestinal perfusions. The plasma concentration-time profiles of cefadroxil were also examined after oral gavage.
The P eff (cm/s) of cefadroxil in wild-type mice was 0.49 × 10(-4) in duodenum, 0.80 × 10(-4) in jejunum, 0.88 × 10(-4) in ileum and 0.064 × 10(-4) in colon. The P eff (cm/s) in PepT1 knockout mice was significantly reduced in small intestine, but not in colon, as shown by values of 0.003 × 10(-4), 0.090 × 10(-4), 0.042 × 10(-4) and 0.032 × 10(-4), respectively. Jejunal uptake of cefadroxil was saturable (Km = 2-4 mM) and significantly attenuated by the sodium-proton exchange inhibitor 5-(N,N-dimethyl)amiloride. Jejunal permeability of cefadroxil was not affected by L-histidine, glycine, cephalothin, p-aminohippurate or N-methylnicotinamide. In contrast, cefadroxil permeability was significantly reduced by glycylproline, glycylsarcosine, or cephalexin. Finally, PepT1 ablation resulted in 23-fold reductions in peak plasma concentrations and 14-fold reductions in systemic exposure of cefadroxil after oral dosing.
The findings are definitive in demonstrating that PepT1 is the major transporter responsible for the small intestinal permeability of cefadroxil as well as its enhanced oral drug performance.
确定肠道 PepT1 对β-内酰胺类抗生素药物头孢羟氨苄的通透性和口服吸收的贡献。
通过原位单次肠灌流在野生型和 PepT1 敲除小鼠中评估头孢羟氨苄的有效渗透（P eff ）。还通过口服灌胃检查了头孢羟氨苄的血浆浓度-时间曲线。
野生型小鼠头孢羟氨苄的 P eff （cm/s）在十二指肠为 0.49×10(-4)，空肠为 0.80×10(-4)，回肠为 0.88×10(-4)，结肠为 0.064×10(-4)。PepT1 敲除小鼠的 P eff （cm/s）在小肠中显著降低，但在结肠中没有降低，分别为 0.003×10(-4)、0.090×10(-4)、0.042×10(-4)和 0.032×10(-4)。头孢羟氨苄在空肠中的摄取是饱和的（Km=2-4 mM），并被钠离子-质子交换抑制剂 5-（N，N-二甲基）阿米洛利显著减弱。头孢羟氨苄在空肠中的通透性不受 L-组氨酸、甘氨酸、头孢噻吩、对氨基马尿酸或 N-甲基烟酰胺的影响。相比之下，头孢羟氨苄的通透性明显被甘氨酰脯氨酸、甘氨酰肌氨酸或头孢氨苄降低。最后，PepT1 缺失导致口服给药后头孢羟氨苄的峰值血浆浓度降低 23 倍，系统暴露量降低 14 倍。
这些发现明确表明，PepT1 是负责头孢羟氨苄的小肠通透性及其增强的口服药物性能的主要转运体。
