Joshi Medha D, Iacoban Paulina, Scheetz Marc H
College of Pharmacy, Midwestern University, Glendale Campus, 19555 N. 59th Avenue, Glendale, AZ 85308, USA.
College of Pharmacy, Midwestern University, Downers Grove Campus, 555 31st Street, Downers Grove, IL 60515, USA.
Pharmaceutics. 2023 May 24;15(6):1582. doi: 10.3390/pharmaceutics15061582.
Vancomycin is a commonly used antibiotic in hospital settings, especially against Methicillin-resistant staphylococcus aureus (MRSA). One of the major adverse events of vancomycin use in adults is kidney injury. The drug concentration, specifically the area under the concentration curve, predicts kidney injury in adults receiving vancomycin. To attempt to reduce vancomycin-induced nephrotoxicity, we have successfully encapsulated vancomycin in polyethylene glycol-coated liposomes (PEG-VANCO-lipo). We have previously carried out in vitro cytotoxicity studies on kidney cells using PEG-VANCO-lipo and found it to be minimally toxic compared to the standard vancomycin. In this study, we have dosed male adult rats with PEG-VANCO-lipo or vancomycin HCl and compared plasma vancomycin concentrations and KIM-1 as an injury biomarker in rat urine. Male Sprague Dawley rats (350 ± 10 g) were administered vancomycin ( = 6) or PEG-VANCO-lipo ( = 6) 150 mg/kg/day for three days using an IV infusion in the left jugular vein catheter. Blood was collected for plasma at 15, 30, 60, 120, 240, and 1440 min after the first and the last IV dose. Urine was collected 0-2, 2-4, 4-8, and 8-24 h after the first and the last IV infusions using metabolic cages. The animals were observed for three days after the last compound administration. Vancomycin was quantified in plasma by LC-MS/MS. Urinary KIM-1 analysis was done by using an ELISA kit. Three days after the last dose, under terminal anesthesia with IP ketamine (65-100 mg/kg) and xylazine (7-10 mg/kg), rats were euthanized. Vancomycin urine and kidney concentrations and KIM-1 were lower on day three in the PEG-Vanco-lipo group compared to the vancomycin group ( < 0.05, ANOVA and/or -test). There was a significant reduction in plasma vancomycin concentration on day one and day three ( < 0.05, -test) in the vancomycin group compared to the PEG-VANCO-lipo group. Vancomycin-loaded PEGylated liposomes resulted in lower levels of kidney injury, as noted by a decrease in KIM-1 values. Moreover, longer circulation in plasma with increased concentration in plasma as opposed to the kidney was observed with the PEG-VANCO-lipo group. The results indicate the high potential of PEG-VANCO-lipo in decreasing the nephrotoxicity of vancomycin clinically.
万古霉素是医院环境中常用的抗生素，尤其用于对抗耐甲氧西林金黄色葡萄球菌（MRSA）。成人使用万古霉素的主要不良事件之一是肾损伤。药物浓度，特别是浓度曲线下面积，可预测接受万古霉素治疗的成人的肾损伤。为了试图降低万古霉素诱导的肾毒性，我们已成功将万古霉素包裹在聚乙二醇包被的脂质体（PEG-VANCO-lipo）中。我们之前使用PEG-VANCO-lipo对肾细胞进行了体外细胞毒性研究，发现与标准万古霉素相比，其毒性极小。在本研究中，我们给雄性成年大鼠注射PEG-VANCO-lipo或盐酸万古霉素，并比较血浆万古霉素浓度以及大鼠尿液中作为损伤生物标志物的KIM-1。雄性Sprague Dawley大鼠（350±10 g）通过左颈静脉导管静脉输注，以150 mg/kg/天的剂量给予万古霉素（n = 6）或PEG-VANCO-lipo（n = 6），持续三天。在首次和末次静脉给药后的15、30、60、120、240和1440分钟采集血液用于检测血浆。使用代谢笼在首次和末次静脉输注后的0 - 2、2 - 4、4 - 8和8 - 24小时收集尿液。在最后一次给药后对动物观察三天。通过LC-MS/MS对血浆中的万古霉素进行定量。使用ELISA试剂盒进行尿KIM-1分析。在末次给药三天后，在腹腔注射氯胺酮（65 - 100 mg/kg）和赛拉嗪（7 - 10 mg/kg）进行终末麻醉下，对大鼠实施安乐死。与万古霉素组相比，PEG-Vanco-lipo组在第三天时万古霉素的尿浓度、肾浓度和KIM-1较低（P < 0.05，方差分析和/或t检验）。与PEG-VANCO-lipo组相比，万古霉素组在第一天和第三天时血浆万古霉素浓度显著降低（P < 0.05，t检验）。如KIM-1值降低所示，负载万古霉素的聚乙二醇化脂质体导致较低水平的肾损伤。此外，观察到PEG-VANCO-lipo组在血浆中的循环时间更长，且血浆中浓度相对于肾脏有所增加。结果表明PEG-VANCO-lipo在临床上降低万古霉素肾毒性方面具有很高的潜力。
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