METABOLISM OF DRUGS BY THE KIDNEY
METABOLISM OF DRUGS BY THE KIDNEY
复制标题
DOI：
10.1038/ki.1980.181
复制
发表时间：
1980-01-01
影响因子：
19.6
通讯作者：
ANDERS, MW
中科院分区：
文献类型：
--
作者：
ANDERS, MW
肾脏有许多明确的生理功能。虽然它们作为药物和化学品及其极性代谢物的排泄器官的作用已得到很好的描述，但它们参与外源性物质的生物转化的情况相对知之甚少。准确地说，我们目前对药物代谢过程的理解主要基于在肝脏中进行的研究。直到最近才对肾脏中的药物代谢进行了详细的研究。这些研究表明，肾脏在影响各种化学品和药物的生物转化方面非常活跃，在某些情况下，超过了肝脏。由于各种原因，了解肾脏在药物和化学品生物转化中的作用很重要。由于肾脏接收心输出量的相当大一部分，因此可以合理地预期它可能对体内药物的总代谢改变做出重大贡献。此外，现在已知许多药物和化学品的毒性作用归因于它们代谢转化为反应性亲电中间体，其在与细胞亲核试剂反应时导致各种有害作用。也许最重要的是认识到活性中间体和关键细胞大分子之间的这种相互作用与致突变和致癌变化密切相关。此外，坏死变化也可能与细胞烷基化有关。因此，对肾脏在药理学和毒理学过程中作用的完整认识依赖于对该器官药物和化学代谢能力的透彻理解。有机化合物的生物转化可以方便地分为氧化、还原、水解和合成或共轭反应。前三个反应是基于所产生的化学变化的类型。合成或结合反应通常涉及化学物质或代谢物与碳水化合物或氨基酸的酶催化结合，并且它们产生高度极性的、易于排泄的代谢物。此外，多种代谢改变非常常见。威廉姆斯在他的经典著作《解毒机制》中提出，许多异生物质的代谢分两步进行[1]。第一阶段称为“I相反应”，包括氧化、还原和水解反应;第二阶段称为“II相反应”，由共轭反应组成，包括例如葡糖苷酸、硫酸盐和马尿酸形成。应该注意的是，虽然在I相反应中产生的代谢物通常比母体化合物毒性更小或活性更低，但可以引用大量的例子，其中代谢物毒性更大且活性更高。出于同样的原因，虽然在II相反应中产生的共轭物通常极性很强且毒性较小，但也存在明显的例外;例如，N-羟基乙酰基-氨基芴的硫酸盐共轭物被认为是该化合物的近似致癌物[5]。
The kidneys have many clearly defined physiologic functions. Although their role as an excretory organ for drugs and chemicals and their polar metabolites is well described, their involvement in the biotransformation of xenobiotics is relatively poorly understood. It is accurate to state that our present understanding of the metabolic processes of drugs is based largely on studies carried out in the liver. Only recently have detailed investigations into drug metabolism in the kidney been carried out. These studies have shown that the kidney is meta-bolically very active in effecting the biotransformation of a variety of chemicals and drugs and, in some cases, surpasses the liver.It is important to understand the role of the kidney in drug and chemical biotransformation for a variety of reasons. Because the kidney receives a substantial portion of the cardiac output, it is reasonable to expect that it may make a significant contribution to the total metabolic alteration of drugs in the body. Furthermore, it is now known that the toxic effects of many drugs and chemicals are attributable to their metabolic conversion to reactive electrophilic intermediates, which, on reaction with cellular nucleophiles, lead to a variety of deleterious effects. Perhaps most important is the appreciation that this interaction between reactive intermediates and critical cellular macromolecules is intimately involved in mutagenic and carcinogenic changes. In addition, necrotic changes may also be associated with cellular alkylation. Thus, a complete perspective on the role of the kidney in pharmacologic and toxicologic processes is dependent on a thorough understanding of the drug and chemical metabolic capabilities of this organ.The biotransformation of organic compounds can be conveniently divided into oxidative, reductive, hydrolytic, and synthetic or conjugation reactions. The first three reactions are based on the type of chemical change produced. Synthetic or conjugation reactions usually involve the enzyme-catalyzed combination of a chemical or a metabolite and a carbohydrate or an amino acid, and they yield highly polar, readily excretable metabolites. Furthermore, multiple metabolic alterations are very common. Williams, in his classic book, Detoxication Mechanisms, suggests that the metabolism of many xenobiotics occurs in two steps [1]. The first, termed “phase I reactions,” includes oxidative, reductive, and hydrolytic reactions; the second, termed “phase II reactions,” consists of conjugative reactions and includes, for example, glucuronide, sulfate, and hippuric acid formation. It should be noted that although the metabolites produced in phase I reactions are frequently less toxic or less active pharmacologically than the parent compound is, abundant examples can be cited where the metabolites are more toxic and more active pharmacologically. By the same token, although the conjugates produced in phase II reactions are usually very polar and less toxic, notable exceptions exist; for example, the sulfate conjugate of N-hydroxyacetyl-aminofluorene is thought to be the proximate carcinogen in the case of this compound [5].