Disease Status Drug Metabolism

一段时间以来，我们小组的一个主要兴趣是营养状态和晚期疾病状态对药物代谢的影响。为此，我们利用了蛋白质卡路里营养不良(PCM)的大鼠模型，并进行了一系列涉及HIV+和癌症患者的临床研究。PCM是一种常见于老年人和癌症患者的营养状态。一组被称为细胞色素P450(细胞色素P450)的药物代谢酶是非常重要的，因此引起了人们的极大兴趣。PCM导致一些药物代谢酶的下调，特别是细胞色素P450。对艾滋病毒和癌症的临床研究涉及对一些酶的分析，对于这些酶，人类群体中存在离散的、由基因决定的亚群。这些遗传多态是由编码这些酶的基因突变产生的，这些突变会导致酶活性降低、增加或缺失。在健康的个体中，这样的代谢活动分为两个定义明确且性质不同的群体：代谢率和代谢程度较差的个体(低代谢者，PM)和具有更快或更广泛新陈代谢(广泛代谢者，EM)的个体。许多CYP酶存在遗传多态。CYP2C19就是这样的一种酶，有2%到5%的高加索人是缓慢代谢者。A？第二阶段？名为乙酰转移酶-2(NAT2)的酶也是多态的，50%到60%的人被归类为缓慢代谢者。无害的药物被用来探测酶的活性，从而检测代谢表型。这项技术涉及给患者口服药物，患者随后将在几个小时后提供尿样。然后，使用高效液相色谱法对样本进行药物及其代谢物分析。这样，咖啡因代谢物比率被用来探测Nat2，而奥美拉唑被用来探测CYP2C19。在健康个体中，只要不存在药物-药物相互作用，代谢表型通常预示着代谢表型。然而，急性和慢性疾病状态会导致代谢酶的相对水平和活性发生变化，这是我们主要关注的问题。 在一项关于疾病对药物代谢影响的临床研究中，对一组HIV+患者的NAT2基因类型和NAT2表型进行了比较。与健康人群不同的是，健康人群可以在基因和表型上分为两个子集，包括？fast？然后呢？穷吗？尽管预期的基因分布为双峰分布，但HIV+人群的乙酰化水平呈表型单峰分布，且偏向于缓慢的乙酰化状态。 在我们的第二项临床研究中，对16例晚期癌症患者进行了基因分型和表型分析。虽然所有16名患者都有广泛的代谢物基因，但有4名患者表现出明显的缓慢表型，而且，患者的表型只有一个群体，偏向于缓慢代谢者状态。在上述两项研究中，使用常规血液学和生化标记物评估肝和肾功能，并被认为是正常的。此外，没有明显的代谢性药物相互作用。因此，我们已经确定，在某些晚期疾病状态，如艾滋病和癌症，通常涉及消瘦综合征，基因可能不能预测相应的代谢表型，两者之间存在不一致。上述研究表明，疾病以及经常伴随疾病的营养状况对人体处理药物的方式有重大影响。确定基因和表型之间的一致性或不一致性为深入研究疾病状态对人类药物代谢的影响提供了一种手段。它是一个单独的探针，可以用来研究一般现象或优化患者特定的临床方案，通过预测药物代谢酶活性的干扰来避免药物毒性。对这一现象的研究仍然是未来疾病对药物代谢影响的临床研究的主要目标。在一项计划中的研究中，将评估使用潜在的治疗剂L-卡尼汀改善癌症浪费(恶病质)的情况。临床状态改善的一个标志将是在这种晚期疾病状态下观察到的代谢基因型和表型之间的不一致的逆转。

For some time, a major interest of our group has been the effect of nutritional state and advanced disease states on drug metabolism. To this end we have utilized a rat model of protein calorie malnutrition (PCM), and a collection of clinical studies involving HIV+ and cancer patients have been carried out. PCM is a nutritional state frequently observed in aged populations and cancer patients. A group of drug metabolizing enzymes called cytochromes P450 (CYPs) are of major importance and thus of major interest. PCM leads to a down-regulation of a number of drug metabolizing enzymes, particularly CYPs. Clinical studies of HIV and cancer have involved the analysis of a selection of enzymes, for which discrete genetically determined subgroups are present in the human population. These genetic polymorphisms are generated by mutations in the genes coding for these enzymes, which cause decreased, increased or absent enzyme activity. In healthy individuals, such metabolic activity falls into two clearly defined and qualitatively different populations: individuals whose rate and extent of metabolism is poor (poor metabolizers, PMs) and those who have faster or more extensive metabolism (extensive metabolizers, EMs). Genetic polymorphisms exist for a number of the CYP enzymes. CYP2C19 is one such enzyme, with 2 to 5% of Caucasians being slow metabolizers. A ?Phase II? enzyme named acetyltransferase-2 (NAT2) is also polymorphic, with 50 to 60% of individuals being classified as slow metabolizers. Innocuous drugs are used to probe enzyme activity, and thus metabolic phenotype. This technique involves oral administration of the drug to a patient who will then provide a urine sample a few hours later. The sample is then analyzed for drug and its metabolites using HPLC. In this way, caffeine metabolite ratios are used to probe for NAT2 and omeprazole is used to probe for CYP2C19. In healthy individuals, as long as there are no drug-drug interactions, metabolic genotype normally predicts metabolic phenotype. However, acute and chronic disease states can lead to changes in the relative levels and activities of metabolizing enzymes and this is our major focus. In a clinical study of disease effects on drug metabolism, NAT2 genotypes were compared to NAT2 phenotypes in a group of HIV+ patients. Unlike a healthy population, which can be genotypically and phenotypically divided into two subsets consisting of ?fast? and ?poor? acetylators, the HIV+ population was phenotypically unimodally distributed, and skewed towards a slow acetylator status, despite the expected bimodal distribution of the genotype. In our second clinical study, sixteen patients with advanced cancer were genotyped and phenotyped. Although all 16 patients had an extensive metabolizer genotype, four patients displayed an apparent slow phenotype and, again, patients phenotypically displayed one population only, skewed towards the slow metabolizer status. In both studies described above, liver and renal function was assessed using routine hematological and biochemical markers, and was considered normal. Additionally, no metabolic drug interactions were apparent. Therefore, we have established that in certain advanced disease states such as AIDS and cancer, often involving wasting syndromes, genotype may not predict the corresponding metabolic phenotype and there is discordance between the two.The studies described above indicate that disease, and the nutritional status that often accompanies disease, has significant impact on the way in which the body handles drugs. Determination of the concordance or discordance between genotype and phenotype provides a means to thoroughly study the effect of disease state on drug metabolism in humans. It is an individual probe that can be used to study the general phenomenon or to optimize patient-specific clinical protocols, avoiding drug toxicity by predicting disturbances in drug metabolizing enzyme activities. The study of this phenomenon continues to be primary objective in future clinical studies of disease effects on drug metabolism. In one such planned study, amelioration of cancer wasting (cachexia) using a potential therapeutic agent, L-carnitine, will be assessed. One marker of improved clinical status will be a reversal of the discordance between metabolic genotype and phenotype observed in this advanced disease state.