In vitro pharmacokinetics of anti-psoriatic fumaric acid esters.
In vitro pharmacokinetics of anti-psoriatic fumaric acid esters.
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DOI：
10.1186/1471-2210-4-22
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发表时间：
2004-10-12
期刊：
影响因子：
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通讯作者：
Nibbering PH
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文献类型：
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作者：
Litjens NH;van Strijen E;van Gulpen C;Mattie H;van Dissel JT;Thio HB;Nibbering PH
牛皮癣是一种慢性炎症性皮肤病，可以通过配制为口服肠溶片的富马酸酯 (FAE) 混合物成功治疗。这些片剂由富马酸二甲酯（DMF）和富马酸单乙酯（MEF）盐组成，其主要生物活性代谢物是富马酸单甲酯（MMF）。人们对这些 FAE 的药代动力学知之甚少。本研究的目的是研究 DMF 水解为 MMF 以及 MMF、DMF 和 MEF 在代表不同身体区室的体外条件下的稳定性。 DMF在碱性环境（pH 8）中水解为MMF，但在酸性环境（pH 1）中则不水解。在这些条件下，MMF 和 MEF 在分析期间（6 小时）保持完整。有趣的是，DMF在pH 7.4的缓冲液中几乎不水解为MMF，但在具有相同pH的人血清中迅速水解。此外，与血清相比，全血中 DMF 的半衰期显着缩短。血清和全血中MMF和MEF的浓度随着时间的延长而降低。这些数据表明循环中的大部分 FAE 由一种或多种类型的血细胞代谢。将纯化的血细胞组分重悬于磷酸盐缓冲盐水（pH 7.4）中进行的其他实验表明，在全血单核细胞/淋巴细胞（而非粒细胞和红细胞）中存在的浓度下，DMF 有效水解为 MMF。此外，与片剂纯成分获得的数据一致，肠溶片在 pH 1 时保持完整，但在 pH 8 时迅速溶解。总而言之，这些体外数据表明 DMF 水解成 MMF 在 pH 8 时迅速发生，类似于小肠内的情况，但在 pH 1 时则不然，类似于胃中的 pH。在两种 pH 值下，MMF 和 MEF 均保持完整。这些数据解释了这样的观察结果：口服FAE后，在人类健康志愿者和牛皮癣患者的循环中很容易检测到MMF和MEF，但不是DMF。
Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments. DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8. Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients.