Drug transport by Organic Anion Transporters (OATs)

被引:284
作者
Burckhardt, Gerhard [1 ]
机构
[1] Univ Med Gottingen, Zentrum Physiol & Pathophysiol, Abt Vegetat Physiol & Pathophysiol, D-37073 Gottingen, Germany
关键词
Kidney; Drug-drug interaction; Renal excretion; beta-lactam antibiotics; Nonsteroidal anti-inflammatory drugs; SLC22; family; Sex differences; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; RENAL CORTICAL OAT1; ESTRONE SULFATE TRANSPORT; SLC22A FAMILY-MEMBERS; SHORT-TERM REGULATION; II RECEPTOR BLOCKERS; TO-BLOOD EFFLUX; MOLECULAR-CLONING; URIC-ACID; FUNCTIONAL-CHARACTERIZATION;
D O I
10.1016/j.pharmthera.2012.07.010
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Common to all so far functionally characterized Organic Anion Transporters (OATs) is their broad substrate specificity and their ability to exchange extracellular against intracellular organic anions. Many OATs occur in renal proximal tubules, the site of active drug secretion. Exceptions are murine Oat6 (nasal epithelium), human OAT7 (liver), and rat Oat8 (renal collecting ducts). In human kidneys, OAT1, OAT2, and OAT3 are localized in the basolateral membrane, and OAT4, OAT10, and URAT1 in the apical cell membrane of proximal tubule cells, respectively. In rats and mice, Oat1 and Oat3 are located basolaterally, and Oat2, Oat5, Oat9, Oat10, and Urat1 apically. Several classes of drugs interact with human OAT1-3, including ACE inhibitors, angiotensin II receptor antagonists, diuretics, HMG CoA reductase inhibitors, beta-lactam antibiotics, antineoplastic and antiviral drugs, and uricosuric drugs. For most drugs, interaction was demonstrated in vitro by inhibition of OAT-mediated transport of model substrates; for some drugs, transport by OATs was directly proven. Based on IC50 values reported in the literature, OAT1 and OAT3 show comparable affinities for diuretics, cephalosporins, and nonsteroidal anti-inflammatory drugs whereas OAT2 has a lower affinity to most of these compounds. Drug-drug interactions at OAT1 and OAT3 may retard renal drug secretion and cause untoward effects. OAT4, OAT10, and URAT1 in the apical membrane contribute to proximal tubular urate absorption, and OAT10 to nicotinate absorption. OAT4 is in addition able to release drugs, e.g. diuretics, into the tubule lumen. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:106 / 130
页数:25
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