Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model.
Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model.
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DOI：
10.1021/mp100132h
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发表时间：
2010-08-02
影响因子：
4.9
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Quan LD;Yuan F;Liu XM;Huang JG;Alnouti Y;Wang D
磁共振成像（MRI）发现N-（2-羟丙基）-甲基丙烯酰胺（HPMA）共聚物在佐剂性关节炎（AA）大鼠模型中具有关节致变性（关节靶向性）。在这篇文章中，我们报道了125i标记的HPMA共聚物-地塞米松缀合物（P-Dex）在AA大鼠体内的定量药代动力学和生物分布（PK/BD）。前药的分子量和Dex含量等结构参数对P-Dex的PK/BD谱有较大影响。分子量（1.4万、2.4万、4.2万g/mol）和Dex含量（0、151、313µmol/g）的增加增强了P-Dex的趋节性。对于分子量和Dex含量最高的缀合物（P-H-MW/Dex），在给药后第7天，每克踝关节滑膜组织注射剂量（ID/g）的百分比为1% g−1，这证实了P-Dex是一种促关节大分子前药。肝脏和脾脏的ID/g值分别为0.51和3.64% g−1。作为抗原呈递器官，脾对前体药物的隔离可能与其与全身性炎症疾病模型相关的异常肿大有关。P-Dex的消炎作用导致脾脏重量逐渐减少，也可能是高ID/g值的原因之一。Dex含量的增加和MW的降低会增加P-Dex在肾脏中的分布。给药后第7天，P-L-Mw （MW = 14000 g/mol， Dex含量= 288µmol/g）的肾脏ID/g值最高（0.91% g−1），这可能表明肾脏小管对缀合物进行了重吸收。P-Dex在心脏和肺部的分布最小。
N-(2-Hydroxypropyl)-methacrylamide (HPMA) copolymer has been found to be arthrotropic (joint-targeting) in adjuvant-induced arthritis (AA) rat model using magnetic resonance imaging (MRI). In this manuscript, we report the quantitative pharmacokinetics and biodistribution (PK/BD) of 125I-labeled HPMA copolymer-dexamethasone conjugate (P-Dex) in AA rats. Structural parameters of the prodrug such as the molecular weight (MW) and Dex content were found to have strong impact on the PK/BD profiles of P-Dex. The increase of MW (14,000 24,000 and 42,000 g/mol) and Dex content (0, 151 and 313 µmol/g) enhances the arthrotropism of P-Dex. For the conjugate with highest MW and Dex content (P-H-MW/Dex), the percentage of injected doses per gram (ID/g) of ankle synovial tissue at day 7th post administration is 1 % g−1, which confirms P-Dex as an arthrotropic macromolecular prodrug. For liver and spleen, the ID/g values are 0.51 and 3.64 % g−1, respectively. As an antigen-presenting organ, the sequestration of the prodrug by spleen may be explained by its abnormal enlargement associated with the systemic inflammatory disease model. Gradual reduction of spleen weight due to the inflammation resolution effect of P-Dex may also contribute to the high ID/g values. Increase of Dex content and reduction of MW would increase P-Dex distribution to kidney. The highest ID/g value for kidney at day 7th post administration (0.91 % g−1) was found with P-L-Mw (MW =14,000 g/mol, Dex content = 288 µmol/g), which may suggest kidney tubuli reabsorption of the conjugates. The P-Dex’ distribution to heart and lung is minimum.
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影响因子：
4.7
作者：
Pechar, M;Ulbrich, K;Schacht, EH
通讯作者：
Schacht, EH
影响因子：
4.9
作者：
Wang D;Miller SC;Liu XM;Anderson B;Wang XS;Goldring SR
通讯作者：
Goldring SR
影响因子：
3.7
作者：
Mitra, A;Nan, A;Line, BR
通讯作者：
Line, BR
DOI：
10.1002/jbm.820211106
发表时间：
1987-11-01
期刊：
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH
影响因子：
--
作者：
SEYMOUR, LW;DUNCAN, R;KOPECEK, J
通讯作者：
KOPECEK, J
影响因子：
6.2
作者：
Scales, CW;Vasilieva, YA;McCormick, CL
通讯作者：
McCormick, CL