Mattarei Andrea, Azzolini Michele, Carraro Massimo, Sassi Nicola, Zoratti Mario, Paradisi Cristina, Biasutto Lucia
CNR Institute of Neuroscience , viale G. Colombo 3, 35121 Padova, Italy.
Mol Pharm. 2013 Jul 1;10(7):2781-92. doi: 10.1021/mp400226p. Epub 2013 Jun 17.
The pharmacological exploitation of resveratrol is hindered by rapid phase-II conjugative metabolism in enterocytes and hepatocytes. One approach to the solution of this problem relies on prodrugs. We report the synthesis and characterization as well as the assessment of in vivo absorption and metabolism of a set of prodrugs of resveratrol in which the OH groups are engaged in the formal (-OCH2OR) or the more labile acetal (-OCH(CH3)OR) linkages. As carrier group (R) of the prodrug, we have used short ethyleneglycol oligomers (OEG) capped by a terminal methoxy group: -O-(CH2CH2O)n-CH3 (n = 0, 1, 2, 3, 4, 6). These moieties are expected to exhibit, to a degree, the favorable properties of longer polyethyleneglycol (PEG) chains, while their relatively small size makes for a more favorable drug loading capacity. After administration of formal-based prodrugs to rats by oral gavage, significant concentrations of derivatives were measured in blood samples over several hours, in all cases except for n = 0. Absorption was maximal for n = 4. Complete deprotection to give resveratrol and its metabolites was however too slow to be of practical use. Administration of the acetal prodrug carrying tetrameric OEG chains resulted instead in the protracted presence of resveratrol metabolites in blood, consistent with a progressive regeneration of the parent molecule from the prodrug after its absorption. The results suggest that prodrugs of polyphenols based on the acetal bond and short ethyleneglycol oligomers of homogeneous size may be a convenient tool for the systemic delivery of the unconjugated parent compound.
白藜芦醇的药理学应用受到肠上皮细胞和肝细胞中快速的II相共轭代谢的阻碍。解决这个问题的一种方法依赖于前药。我们报告了一组白藜芦醇前药的合成、表征以及体内吸收和代谢评估，其中羟基参与了形式上的（-OCH2OR）或更不稳定的缩醛（-OCH(CH3)OR）键合。作为前药的载体基团（R），我们使用了由末端甲氧基封端的短乙二醇低聚物（OEG）：-O-(CH2CH2O)n-CH3（n = 0、1、2、3、4、6）。预计这些部分在一定程度上会表现出较长聚乙二醇（PEG）链的有利特性，而它们相对较小的尺寸使得药物负载能力更有利。通过口服灌胃给大鼠施用基于形式的前药后，除了n = 0的所有情况下，在数小时内血液样本中都检测到了显著浓度的衍生物。n = 4时吸收最大。然而，完全脱保护生成白藜芦醇及其代谢产物的速度太慢，不具有实际应用价值。相反，施用带有四聚体OEG链的缩醛前药导致白藜芦醇代谢产物在血液中持续存在，这与前药吸收后母体分子从前药中逐渐再生一致。结果表明，基于缩醛键和均一尺寸的短乙二醇低聚物的多酚前药可能是一种方便的工具，用于全身递送未共轭的母体化合物。
