Schmucker D L
Cell Biology & Aging Section (151E), Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Drugs Aging. 2001;18(11):837-51. doi: 10.2165/00002512-200118110-00005.
Aging is accompanied by marked changes in the physiology of many organs, as well as in their constituent cells. These nonpathological alterations in structure and/or function may affect normal physiological processes in the elderly (individuals > 65 years), for example drug disposition. The liver plays a major role in drug clearance and aging has been reported to diminish this hepatic capacity, particularly the clearance of drugs that undergo mandatory oxidation by the microsomal cytochrome P450-dependent mono-oxygenase systems. Liver volume and blood flow decline with age in humans and, no doubt, this contributes to the diminished clearance of drugs that exhibit first-pass kinetic profiles. Changes in liver morphology with aging that have been described in rodents are limited to the hepatocytes, for example accumulation of dense bodies and loss of smooth surfaced endoplasmic reticulum. There is no evidence that the increase in intracellular lipofuscin adversely affects hepatocyte functions. A number of studies have documented significant age-related declines in the amounts, specific activities and rates of induction of liver microsomal mono-oxygenases in inbred male rats. On the basis of a variety of clinical tests, most liver functions in humans appear to be well preserved. The most remarkable characteristic of liver function in the elderly is the increase in interindividual variability, a feature that may obscure age-related differences. Most in vitro studies using nonhuman primate or human liver tissue did not detect age-related deficiencies in cytochrome P450-dependent microsomal mono-oxygenases. On the other hand, there have been recent reports of age-related, but not gender-related, declines in the in vitro activities of several human liver mono-oxygenases, for example the cytochrome P450 isoform CYP3A. Nevertheless, reduced liver volume and blood flow in the elderly permit the reconciliation of: the in vivo clinical pharmacokinetic data indicative of reduced hepatic drug clearance; and the absence of significant age-related declines in the amounts or in vitro activities of liver microsomal mono-oxygenases.
衰老伴随着许多器官及其组成细胞生理学的显著变化。这些结构和/或功能上的非病理性改变可能会影响老年人（年龄>65岁）的正常生理过程，例如药物处置。肝脏在药物清除中起主要作用，据报道衰老会降低这种肝脏能力，特别是微粒体细胞色素P450依赖性单加氧酶系统进行强制氧化的药物的清除。人类肝脏体积和血流量随年龄下降，毫无疑问，这导致了具有首过动力学特征的药物清除率降低。在啮齿动物中描述的肝脏形态随衰老的变化仅限于肝细胞，例如致密体的积累和平滑面内质网的丧失。没有证据表明细胞内脂褐素的增加会对肝细胞功能产生不利影响。多项研究记录了近交系雄性大鼠肝脏微粒体单加氧酶的数量、比活性和诱导率与年龄相关的显著下降。基于各种临床试验，人类的大多数肝功能似乎保存良好。老年人肝功能最显著的特征是个体间变异性增加，这一特征可能掩盖与年龄相关的差异。大多数使用非人类灵长类动物或人类肝脏组织的体外研究未检测到细胞色素P450依赖性微粒体单加氧酶与年龄相关的缺陷。另一方面，最近有报道称几种人类肝脏单加氧酶的体外活性与年龄相关但与性别无关的下降，例如细胞色素P450同工型CYP3A。然而，老年人肝脏体积和血流量的减少使得以下情况能够得到解释：体内临床药代动力学数据表明肝脏药物清除率降低；以及肝脏微粒体单加氧酶的数量或体外活性没有与年龄相关的显著下降。
