Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats.
Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel's tissue distribution in Sprague Dawley rats.
复制标题
Oxycodone 诱导 P-糖蛋白 (ABCB1) 过度表达并影响紫杉醇在 Sprague Dawley 大鼠中的组织分布。
DOI：
10.1002/jps.20893
复制
发表时间：
2007
影响因子：
3.8
通讯作者：
Eddington,NatalieD
中科院分区：
文献类型：
--
作者：
Hassan,HazemE;Myers,AlanL;Lee,InsongJ;Coop,Andrew;Eddington,NatalieD
先前的研究表明，P糖蛋白（P‐gp）调节许多化合物的PK/PD，包括阿片受体激动剂和化疗药物。本研究的目的是评估羟考酮对P - gp的亲和力状态、P - gp的表达和紫杉醇在羟考酮处理大鼠中的组织分布。采用P‐gp atp酶测定、Caco‐2经上皮通透性研究和mdr1a/b（−/−）小鼠来评估氧可酮的P‐gp亲和状态。Western blot检测P‐gp的表达，液体闪烁计数器检测[14C]紫杉醇在肝、肾、脑和血浆组织中的分布。羟考酮以浓度依赖性的方式刺激P - gp atp酶活性。与p‐gp抑制剂维拉帕米预孵育后，羟考酮的Caco‐2分泌转运从3.64 × 10−5cm/s降至1.96 × 10−5cm/s （p< 0.05）。脑内氧可酮inmdr1a/b（+/+）水平未检测到（<15 ng/mL），而inmdr1a/b（−/−）平均水平为115±39 ng/mL。氧可酮组大鼠P - gp蛋白水平升高1.3 ~ 4.0倍，紫杉醇组织分布减少38 ~ 90% （P < 0.05）。这些发现表明，羟考酮是P - gp底物，诱导P - gp过表达，并以可能影响其化疗活性的方式影响紫杉醇的组织分布。©2007 Wiley‐Liss, Inc.和美国药剂师协会[J] .药学杂志96:2494-2506,2007
Previous studies suggest that P‐glycoprotein (P‐gp) modulates the PK/PD of many compounds including opioid agonists and chemotherapeutic agents. The objective of this study was to assess the P‐gp affinity status of oxycodone, the P‐gp expression, and the paclitaxel's tissue distribution in oxycodone‐treated rats. P‐gp ATPase assay, Caco‐2 transepithelial permeability studies, andmdr1a/b(−/−) mice were used to assess the P‐gp affinity status of oxycodone. P‐gp expression was determined by Western blot analysis while [14C] paclitaxel's distributions in the liver, kidney, brain, and plasma tissues were determined by liquid scintillation counter. Oxycodone stimulated the P‐gp ATPase activity in a concentration‐dependant manner. The Caco‐2 secretory transport of oxycodone was reduced from 3.64 × 10−5to 1.96 × 10−5cm/s (p< 0.05) upon preincubation with the P‐gp inhibitor, verapamil. The brain levels of oxycodone inmdr1a/b(+/+) were not detectable (<15 ng/mL) while inmdr1a/b(−/−) the average levels were 115 ± 39 ng/mL. The P‐gp protein levels were increased by 1.3–4.0 folds while paclitaxel's tissue distributions were decreased by 38–90% (p< 0.05) in oxycodone‐treated rats. These findings display that oxycodone is a P‐gp substrate, induces overexpression of P‐gp, and affects paclitaxel's tissue distribution in a manner that may influence its chemotherapeutic activity. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2494–2506, 2007