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To investigate the ability of microdialysis technique to detect in vivo skin metabolism of dexamethasone sodium phosphate.

机译：研究微透析技术检测体内地塞米松磷酸钠皮肤代谢的能力。

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摘要

Drugs are often applied to the skin to target local diseases or to be absorbed systemically as an alternative to oral or intravenous administration. The epidermis and dermis components of the skin contains a number of enzymes for either Phase I metabolism (e.g., CYP450, esterases, hydrolases, alcohol and aldehyde dehydrogenase) and Phase II (e.g., glutathione transferases, glucoronyl transferases or N-acetyl transferases). The metabolism of xenobiotic compounds in the skin is primarily intended to detoxify reactive chemicals, but in some cases results in sensitization reactions or enhanced local activity or systemic toxicity. Therefore the knowledge of cutaneous metabolism in the skin is a critical determinant for the safe and efficient use of local skin treatment with topically applied drugs.;Dexamethasone sodium phosphate (DSP) is a water-soluble prodrug of Dexamethasone (DXM) as it is readily converted to the active form (DXM) in-vivo by esterases. DSP iontophoresis is routinely used in clinical practice by physiotherapists to decrease pain and inflammation in musculoskeletal disorders. Recently, in our laboratory we studied the kinetic of DSP in rabbit and human skin following iontophoresis using cutaneous microdialysis as sampling technique. During these studies we have detected DXM together with DSP in most dialysate samples. The objective of the research presented in this thesis is to find out whether the detected DXM is due to skin metabolism or to chemical degradation as DSP converts to DXM also in solution. Three female pathogen-free New Zealand albino rabbits were inserted with three microdialysis probes according to a cross over design. The probes were perfused with DSP solutions for 4 hours. The same procedure was repeated inserting the microdialysis probes in a hollow box that contained only air. Microdilaysis samples for both rabbit and hollow box were collected at predetermined frequency for four hours and analyzed by a validated, reversed phase chromatography with UV detector. Mobile phase composition was 61% methanol: 39% 10 mM Tetrabutyl ammonium hydrogen sulphate (pH 3) for both analyte. Calibration curves were linear in the range 10000-100 ng/mL and 10000-50 ng/mL for DSP and DXM respectively. Dialysate data for rabbit and hollow box were analyzed for DSP and DXM content by HPLC. The percentage DXM detected in the dialysates from the rabbits' skin was then compared with that measured from the boxes using the statistical packages SAS and SPSS. The results of this study show that the conversion of DSP to DXM was always slightly higher in rabbits than that in the hollow boxes but was not statistically significant (P> 0.05) possibly due to a large variability in the data. In conclusion, most of the DXM detected in skin dialysates is due to natural degradation of DSP in solution rather than to skin metabolism.
机译：作为口服或静脉内给药的替代方法，通常将药物涂在皮肤上以靶向局部疾病或被全身吸收。皮肤的表皮和真皮成分包含许多酶，用于I期代谢（例如CYP450，酯酶，水解酶，乙醇和醛脱氢酶）和II期（例如谷胱甘肽转移酶，葡糖醛酸转移酶或N-乙酰基转移酶）。异种生物化合物在皮肤中的代谢主要旨在使活性化学物质解毒，但在某些情况下会导致过敏反应或增强的局部活性或全身毒性。因此，皮肤中皮肤新陈代谢的知识是安全和有效使用局部应用药物进行局部皮肤治疗的关键决定因素;地塞米松磷酸钠（DSP）是地塞米松（DXM）的水溶性前药，因为它很容易使用通过酯酶体内转化为活性形式（DXM）。理疗师通常在临床实践中使用DSP离子电渗疗法来减轻肌肉骨骼疾病的疼痛和炎症。最近，在我们的实验室中，我们使用皮肤微透析作为采样技术研究了离子电渗疗法后兔和人皮肤中DSP的动力学。在这些研究中，我们在大多数透析液样品中检测到了DXM和DSP。本文提出的研究目的是找出检测到的DXM是由于皮肤代谢还是化学降解，因为在溶液中DSP也转化为DXM。根据交叉设计，将三只无病原体的雌性新西兰白化兔子与三只微透析探针一起插入。用DSP溶液灌注探针4小时。重复相同的程序，将微透析探针插入仅包含空气的空心箱中。以预定的频率收集兔子和空心盒子的微渗析样品四个小时，并通过经过验证的反相色谱仪和紫外检测器进行分析。两种分析物的流动相成分均为61％甲醇：39％10 mM四丁基硫酸氢铵（pH 3）。对于DSP和DXM，校准曲线分别在10000-100 ng / mL和10000-50 ng / mL范围内呈线性。通过HPLC分析兔子和空心箱的透析液数据中DSP和DXM的含量。然后，使用统计软件包SAS和SPSS将在兔子皮肤透析液中检测到的DXM百分比与在盒子中测得的DXM百分比进行比较。这项研究的结果表明，兔子中DSP到DXM的转化率总是比中空盒中的略高，但没有统计学意义（P> 0.05），这可能是由于数据的巨大差异所致。总之，在皮肤透析液中检测到的大多数DXM是由于溶液中DSP的自然降解，而不是皮肤代谢。

著录项

  • 作者

    Patel, Komalkumar.;

  • 作者单位

    Long Island University, The Brooklyn Center.;

  • 授予单位 Long Island University, The Brooklyn Center.;
  • 学科 Health Sciences Pharmacology.;Health Sciences Pharmacy.
  • 学位 M.S.
  • 年度 2012
  • 页码 104 p.
  • 总页数 104
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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