Impact of genetic knockout of PEPT2 on cefadroxil pharmacokinetics, renal tubular reabsorption, and brain penetration in mice
Impact of genetic knockout of PEPT2 on cefadroxil pharmacokinetics, renal tubular reabsorption, and brain penetration in mice
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DOI：
10.1124/dmd.107.015263
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发表时间：
2007-07-01
影响因子：
3.9
通讯作者：
Smith, David E.
中科院分区：
文献类型：
--
作者：
Shen, Hong;Ocheltree, Scott M.;Smith, David E.
本研究的目的是检查PEPT 2（SLC 15家族的质子偶联寡肽转运蛋白）对抗生素头孢羟氨苄在体内（特别是肾脏和大脑）的处置的作用。以1、12.5、50和100 nmol/g体重静脉推注给予[H-3]头孢羟氨苄后，在野生型和PEPT 2缺失小鼠中进行了药代动力学、组织分布和肾脏清除率研究。还在不存在和存在丙磺舒和奎宁的情况下进行了研究。头孢羟氨苄处置动力学在研究的剂量范围内（1 - 100 nmol/g）明显呈非线性，这归因于饱和肾小管分泌和抗生素的重吸收。静脉推注1 nmol/ g头孢羟氨苄后，与野生型动物相比，PEPT 2缺失小鼠的总清除率高3倍，全身药物浓度低3倍。肾清除率研究进一步证明，在PEPT 2缺失小鼠与野生型小鼠中，头孢羟氨苄的肾重吸收几乎完全消除（3%与70%，p < 0.001）。在野生型小鼠中，70%的头孢羟氨苄被重吸收，PEPT 2占95%，PEPT 1占重吸收底物的5%。组织分布研究表明，PEPT 2对头孢羟氨苄组织暴露具有显著影响，尤其是在脑中，其中与野生型动物相比，PEPT 2缺失小鼠中头孢羟氨苄的脑脊液（CSF）与血液浓度比高6倍。这些结果表明，肾脏PEPT 2几乎完全负责头孢羟氨苄在肾脏中的重吸收，脉络丛PEPT 2限制了头孢羟氨苄（可能还有其他氨基头孢菌素）在CSF中的暴露。
The aim of this study was to examine the role of PEPT2, a protoncoupled oligopeptide transporter of the SLC15 family, on the disposition of the antibiotic cefadroxil in the body, particularly the kidney and brain. Pharmacokinetic, tissue distribution, and renal clearance studies were performed in wild-type and PEPT2 null mice after intravenous bolus administration of [H-3] cefadroxil at 1, 12.5, 50, and 100 nmol/g body weight. Studies were also performed in the absence and presence of probenecid and quinine. Cefadroxil disposition kinetics was clearly nonlinear over the dose range studied (1 - 100 nmol/g), which was attributed to both saturable renal tubular secretion and reabsorption of the antibiotic. After an intravenous bolus dose of 1 nmol/ g cefadroxil, PEPT2 null mice exhibited a 3-fold greater total clearance and 3-fold lower systemic concentrations of drug compared with wild-type animals. Renal clearance studies further demonstrated that the renal reabsorption of cefadroxil was almost completely abolished in PEPT2 null versus wild-type mice (3% versus 70%, p < 0.001). Of the 70% of cefadroxil reabsorbed in wild-type mice, PEPT2 accounted for 95% and PEPT1 accounted for 5% of reabsorbed substrate. Tissue distribution studies indicated that PEPT2 had a dramatic effect on cefadroxil tissue exposure, especially in brain where the cerebrospinal fluid (CSF)-to-blood concentration ratio of cefadroxil was 6-fold greater in PEPT2 null mice compared with wild- type animals. These findings demonstrate that renal PEPT2 is almost entirely responsible for the reabsorption of cefadroxil in kidney and that choroid plexus PEPT2 limits the exposure of cefadroxil (and perhaps other aminocephalosporins) in CSF.