Langman L J, LeGatt D F, Yatscoff R W
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
Ther Drug Monit. 1994 Dec;16(6):602-7. doi: 10.1097/00007691-199412000-00012.
RS-61443 (RS) a morpholinoethyl ester of mycophenolic acid (MPA), can be considered a prodrug, as immunosuppressive activity is expressed only after hydrolysis to MPA upon absorption. Little is known about the blood distribution of MPA; such information would have an impact on the medium used for analysis of the drug in clinical trials. This was investigated by spiking whole blood having an initial temperature of either 4 degrees or 22 degrees C with increasing amounts of MPA ranging from 100 to 10,000 micrograms/L. These drug concentrations span the range seen when immunosuppressive doses of the RS are administered. This was followed by incubation of the blood at 37 degrees C for 0-120 min prior to separation of the cells. The drug concentration was measured in the plasma and whole blood fractions by high-performance liquid chromatography. MPA was almost exclusively found in the plasma fraction and did not exhibit any temperature or concentration dependence. The free or unbound fraction of MPA over the same concentration range was determined by ultracentrifugation and demonstrated a concentration dependence ranging from 7.2 to 16.5% of total drug for a concentration range spanning 500-10,000 micrograms/L. The drug was found to be primarily associated with the non-albumin proteins in the plasma. Less than 10% of the drug was found to be bound to lipoproteins. The data suggest that from an analytical standpoint, plasma, rather than whole blood, would be the most suitable medium for analysis because of the higher concentrations of the drug found in this fraction.
霉酚酸（MPA）的吗啉代乙酯RS-61443（RS）可被视为前体药物，因为只有在吸收后水解为MPA才表现出免疫抑制活性。关于MPA的血液分布知之甚少；此类信息会对临床试验中分析该药物所用的介质产生影响。通过向初始温度为4℃或22℃的全血中加入100至10,000微克/升不等的MPA进行研究。这些药物浓度涵盖了给予RS免疫抑制剂量时所见的范围。随后在37℃孵育血液0至120分钟，然后分离细胞。通过高效液相色谱法测量血浆和全血部分中的药物浓度。MPA几乎完全存在于血浆部分，且未表现出任何温度或浓度依赖性。通过超速离心法测定相同浓度范围内MPA的游离或未结合部分，结果表明，在500至10,000微克/升的浓度范围内，总药物的浓度依赖性为7.2%至16.5%。发现该药物主要与血浆中的非白蛋白蛋白结合。发现不到10%的药物与脂蛋白结合。数据表明，从分析角度来看，血浆而非全血是最适合分析的介质，因为该部分中药物浓度更高。
