Babu N Suresh, Malik J K, Rao G S, Aggarwal Manoj, Ranganathan V
Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar.
Arch Environ Contam Toxicol. 2006 May;50(4):587-93. doi: 10.1007/s00244-005-1069-5. Epub 2006 Jan 30.
Assessment of deleterious effects produced by concurrent exposure to commonly encountered chemicals is of great concern to find out toxicological consequences arising as a result of their interactions and for a more comprehensive management of chemical-induced untoward effects. The naturally occurring heavy metal arsenic is present in food and water. Malathion is one of the most widely used pesticides in agriculture and public health practices worldwide. Humans, animals, and birds are exposed to these chemicals through environmental processes. Since arsenic and malathion are shown to exert an inhibitory effect on cytochrome P450 activities, their continuous exposure may alter the disposition kinetics of drugs that are predominantly metabolized hepatically. The current study was undertaken to evaluate the impact of subchronic exposure of arsenic, malathion, and their combination on the disposition kinetics of widely used fluoroquinolone antimicrobial pefloxacin in chickens. Broiler chickens were exposed to either arsenic (50 ppm), malathion (500 ppm), or arsenic (50 ppm) plus malathion (500 ppm). Arsenic and malathion were given in drinking water and feed, respectively. Following 28 days of exposure, all birds received a single oral dose of pefloxacin (10 mg/kg) and the plasma concentrations and the disposition kinetic parameters of the drug were determined. In the birds not exposed to arsenic and/or malathion, the elimination half-life (t(1/2beta)), area under the plasma concentration-time curve (AUC), maximum plasma drug concentration (C(max)), mean residence time (MRT), and bioavailability of pefloxacin were 8.46 +/- 0.24 h, 39.06 +/- 1.13 microg.h.ml(-1), 2.69 +/- 0.19 microg.ml(-1), 12.29 +/- 0.48 h, and 60.52 +/- 1.74%, respectively. Exposure to arsenic was associated with a significant increase in C(max) (4.28 +/- 0.45 microg.ml(-1)) and a nonsignificant increase in the values of AUC (48.96 +/- 2.55 microg.h.ml(-1)) and bioavailability (74.55 +/- 3.8 %) of pefloxacin. The values of AUC (51.62 +/- 4.76 microg.h.ml(-1)), t(1/2beta) (12.57 +/- 1.26 h), MRT (19.94 +/- 1.99 h), and bioavailability (78.59 +/- 7.25 %) of pefloxacin were significantly increased in malathion-exposed birds. Concomitant exposure to arsenic and malathion did not affect the disposition kinetic variables of pefloxacin. The study shows that subchronic malathion exposure significantly alters the elimination kinetics of pefloxacin. Following concurrent exposure, arsenic nullifies the malathion-induced changes in disposition kinetics of pefloxacin by possibly diminishing the cytochrome P450-catalyzed bioactivation of malathion.
评估同时接触常见化学物质所产生的有害影响，对于查明因它们相互作用而产生的毒理学后果以及更全面地管理化学物质诱发的不良影响至关重要。天然存在的重金属砷存在于食物和水中。马拉硫磷是全球农业和公共卫生实践中使用最广泛的农药之一。人类、动物和鸟类通过环境过程接触这些化学物质。由于砷和马拉硫磷已被证明对细胞色素P450活性有抑制作用，它们的持续接触可能会改变主要经肝脏代谢的药物的处置动力学。本研究旨在评估亚慢性接触砷、马拉硫磷及其组合对广泛使用的氟喹诺酮类抗菌药物培氟沙星在鸡体内处置动力学的影响。将肉鸡分别暴露于砷（50 ppm）、马拉硫磷（500 ppm）或砷（50 ppm）加马拉硫磷（500 ppm）。砷和马拉硫磷分别通过饮用水和饲料给予。暴露28天后，所有鸡只单次口服给予培氟沙星（10 mg/kg），并测定药物的血浆浓度和处置动力学参数。在未接触砷和/或马拉硫磷的鸡只中，培氟沙星的消除半衰期（t(1/2β)）、血浆浓度-时间曲线下面积（AUC）、最大血浆药物浓度（C(max)）、平均驻留时间（MRT）和生物利用度分别为8.46±0.24小时、39.06±1.13微克·小时·毫升⁻¹、2.69±0.19微克·毫升⁻¹、12.29±0.48小时和60.52±1.74%。接触砷与培氟沙星的C(max)显著升高（4.28±0.45微克·毫升⁻¹）以及AUC值（48.96±2.55微克·小时·毫升⁻¹）和生物利用度（74.55±3.8%）非显著升高有关。在接触马拉硫磷的鸡只中，培氟沙星的AUC值（51.62±4.76微克·小时·毫升⁻¹）、t(1/2β)（12.57±1.26小时）、MRT（19.94±1.99小时）和生物利用度（78.59±7.25%）显著升高。同时接触砷和马拉硫磷并未影响培氟沙星的处置动力学变量。该研究表明，亚慢性接触马拉硫磷会显著改变培氟沙星的消除动力学。同时接触后，砷可能通过减少细胞色素P450催化的马拉硫磷生物活化作用，抵消了马拉硫磷诱导的培氟沙星处置动力学变化。
