Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study

Posaconazole is an antifungal with a wide-spectrum of activity against common and emerging fungal pathogens. In this randomised, open-label, two-way crossover study, the potential for drug interactions with posaconazole via the cytochrome P450 (CYP450) enzyme pathway was evaluated. Thirteen subjects received posaconazole tablets (2×100 mg) once daily for 10 days or no treatment; following a 14-day washout period, subjects were crossed over to the alternate treatment. The inhibition spectra of posaconazole were examined using a cocktail of the following probe substrates: caffeine (CYP1A2), tolbutamide (CYP2C8/9), dextromethorphan (CYP2D6 and total CYP3A4), chlorzoxazone (CYP2E1), and midazolam (hepatic CYP3A4). Except for midazolam, which was intravenously infused on Day 10, the cocktail probes were administered simultaneously on Day 9 during both treatment periods. Blood and urine samples were collected at specified times to quantitate probe substrates and/or metabolites. Based on insignificant differences in mean probe ratios, posaconazole did not inhibit CYP1A2, 2C8/9, 2D6, or 2E1. However, the midazolam AUC_(tf) was higher in the posaconazole than no-treatment group (93.4 ng h/ml versus 51.4 ng h/ml, P<0.01), indicating inhibition of hepatic CYP3A4. Drug interactions mediated by various CYP450 are common with the currently available triazole antifungals, however these results suggest that posaconazole may have an improved and more narrow drug interaction profile (CYP3A4 only) compared with other triazoles.     

龙眼参对小鼠化学性肝损伤的保护作用及其机制研究

目的 :研究龙眼参对小鼠化学性肝损伤的保护作用及其机制。方法 :分别对四氯化碳、硫代乙酰胺和对乙酰氨基酚所致小鼠化学性肝损伤模型进行分组对照实验 ,并对各项相关指标进行测定和比较。结果 :与模型组比较 ,龙眼参治疗组ALT活性明显降低 ;肝脏细胞色素P450 及细胞色素b5 含量升高 ;肝组织丙二醛的含量显著降低 ;苯胺羟化酶及氨基比林 -N -去甲基酶活性增强 ;肝微粒体Ca2 + -ATP酶的活性明显降低 ;谷胱甘肽及谷胱甘肽过氧化物酶的水平明显提高。结论 :龙眼参对小鼠化学性肝损伤具有保护作用 ,其机制可能与其抗氧自由基、抑制脂质过氧化、诱导肝药酶活性和阻滞Ca2 +通道的作用有关。     

柑橘类果汁对大鼠细胞色素P450 3A的抑制与果汁中呋喃香豆素组成的相关性

目的：呋喃香豆素类(补骨脂素类)是导致葡萄柚汁与药物相互作用的重要成分。本研究拟调查该类化合物在其它柑橘类果汁中的存在，并比较这些果汁对细胞色素P450(CYP)3A活性的抑制强度。方法：用梯度高压液相色谱法测定柑橘类的鲜榨果汁中6种呋喃香豆素化合物的组成与含量。以雄性Sprague-Dawley大鼠肝微粒体的睾酮613．羟化活性测试每种果汁对CYP3A的抑制作用。结果：与葡萄柚汁比较，Jaffa sweetie果汁中呋喃香豆素的组成与含量基本相同，对CYP3A的抑制强度也相当；日本红柚、溪蜜柚和金柚的果汁中呋喃香豆素组成相似但含量较低，对CYP3A的抑制强度也较弱；常山胡柚、甜橙与宽皮橘果汁中呋喃香豆素种类少且含量极低。且多数对CYP3A无抑制作用。结论：根据呋喃香豆素组成可以预测柑橘类果汁因为抑制CYP3A引起的药物相互作用；琯溪蜜柚及近缘品种的果汁可能导致类似于葡萄柚汁的药物相互作用，有必要在临床上加以验证。     

细胞色素P450与药物代谢的研究现状

细胞色素P450(CYP)在众多中西药物代谢中起着非常重要的作用。本文综述了与药物代谢相关的CYP亚型、CYP与药物相互作用的关系及中药对CYP的影响，旨在合理解释和预测临床上药物间相互作用和药物不良反应等。同时选择适当的药物作为探针来评价CYP的活性，为实现临床个体化给药提供科学依据。     

Glutathione depletion is a major determinant of inhaled naphthalene respiratory toxicity and naphthalene metabolism in mice.

Naphthalene (NA) is metabolized to highly reactive intermediates that are primarily detoxified by conjugation to glutathione (GSH). Intraperitoneal administration of naphthalene causes substantial loss of both hepatic and respiratory GSH, yet only respiratory tissues are injured in mice. The liver supplies GSH to other organs via the circulation, making it unclear whether respiratory GSH losses reflect in situ respiratory depletion or decreased hepatic supply. To address this concern, mice were exposed to naphthalene by inhalation (1.5-15 ppm; 2-4 h), thereby bypassing first-pass hepatic involvement. GSH levels and histopathology were monitored during the first 24 h after exposure. Half of the mice were given the GSH depletor diethylmaleate (DEM) 1 hour before naphthalene exposure. Lung and nasal GSH levels rapidly decreased (50-90%) in mice exposed to 15 ppm naphthalene, with cell necrosis throughout the respiratory tract becoming evident several hours later. Conversely, 1.5 ppm naphthalene caused moderate GSH loss and only injured the nasal olfactory epithelium. Neither naphthalene concentration depleted hepatic GSH. Animals pretreated with DEM showed significant GSH loss and injury in nasal and intrapulmonary airway epithelium at both naphthalene concentrations. DEM treatment, perhaps by causing significant GSH loss, decreased water-soluble naphthalene metabolite formation by 48% yet increased NA-protein adducts 193%. We conclude that (1) GSH depletion occurs in airways independent of hepatic function; (2) sufficient GSH is not supplied by the liver to maintain respiratory GSH pools, or to prevent injury from inhaled naphthalene; and (3) GSH loss precedes injury and increases protein adduct formation.     

The Biological Actions of Dehydroepiandrosterone Involves Multiple Receptors

Dehydroepiandrosterone has been thought to have physiological functions other than as an androgen precursor. The previous studies performed have demonstrated a number of biological effects in rodents, such as amelioration of disease in diabetic, chemical carcinogenesis, and obesity models. To date, activation of the peroxisome proliferators activated receptor alpha, pregnane X receptor, and estrogen receptor by DHEA and its metabolites have been demonstrated. Several membrane-associated receptors have also been elucidated leading to additional mechanisms by which DHEA may exert its biological effects. This review will provide an overview of the receptor multiplicity involved in the biological activity of this sterol.     

Human Cytochrome P450 Family 4 Enzymes: Function,Genetic Variation and Regulation

The microsomal cytochrome P450 (CYP) family 4 monooxygenases are the major fatty acid ω-hydroxylases. These enzymes remove excess free fatty acids to prevent lipotoxicity, catabolize leukotrienes and prostanoids, and also produce bioactive metabolites from arachidonic acid ω-hydroxylation. In addition to endogenous substrates, recent evidence indicates that CYP4 monooxygenases can also metabolize xenobiotics, including therapeutic drugs. This review focuses on human CYP4 enzymes and updates current knowledge concerning catalytic activity profiles, genetic variation and regulation of expression. Comparative differences between the human and rodent CYP4 enzymes regarding catalytic function and conditional expression are also discussed.     

Integration of toxicological approaches with “omic” and related technologies to elucidate mechanisms of carcinogenic action: Propiconazole,an example

The field of mechanistic chemical carcinogenesis has evolved with the advent and advances in genomic, proteomic and metabolomic technologies. These advances allow mechanistic events along the process of exposure to frank tumors to be studied in great detail. Herein is reviewed an example of this approach using, propiconazole, a triazole-containing antifungal agent that is a mouse hepatocarcinogen. This review will highlight those toxicological, genomic, proteomic and metabolomic findings in mice that were used to describe a set of linked events that lead to propiconazole-induced hepatocarcinogenesis. Independent experimental proof of many of these events is presented that solidified this proposed mechanism of carcinogenic action for propiconazole.     

Loss of orally administered drugs in GI tract

The aim of this review is to provide a broad perspective on intestinal absorption and the impact of intestinal first-pass metabolism on both clearance and drug–drug interaction prediction along with its historical perspectives. The review also considers abilities to bridge the gap between the increasing amount of intestinal in vitro data and the importance of intestinal first-pass metabolism in vivo. The significance of efflux transporters on the intestinal absorption is also discussed.