Department of Renal and Body Fluid Physiology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Street, 02-106, Warsaw, Poland.
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 5a Pawinskiego Street, 02-106, Warsaw, Poland.
Hypertens Res. 2018 Apr;41(4):234-245. doi: 10.1038/s41440-018-0011-y. Epub 2018 Feb 13.
Novel lipid-based carriers, composed of cationic derivatives of polyisoprenoid alcohols (amino-prenols, APrens) and 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE), were designed. The carriers, which were previously shown to be nontoxic to living organisms, were now tested if suitable for administration of candesartan, an antihypertensive drug. Spontaneously hypertensive rats (SHR) received injections of candesartan (0.1 mg/kg body weight per day; s.c.) in freshly prepared carriers for two weeks. The rats' arterial pressure was measured by telemetry. Urine and blood collection were performed in metabolic cages. In a separate group of SHR, the pharmacokinetics of the new formulation was evaluated after a single subcutaneous injection. The antihypertensive activity of candesartan administered in DOPE dispersions containing APrens was distinctly greater than that of candesartan dispersions composed of DOPE only or administered in the classic solvent (sodium carbonate). The pharmacokinetic parameters clearly demonstrated that candesartan in APren carriers reached the bloodstream more rapidly and in much greater concentration (almost throughout the whole observation) than the same drug administered in dispersions of DOPE only or in solvent. Serum creatinine (P) decreased significantly only in the group receiving candesartan in carriers with APrens (from 0.80 ± 0.04 to 0.66 ± 0.09 mg/dl; p < 0.05), whereas in the other groups P remained at the same level after treatment. Moreover, the new derivatives increased the loading capacity of the carriers, which is a valuable feature for any drug delivery system. Taken together, our findings led us to conclude that APrens are potentially valuable components of lipid-based drug carriers.
新型脂质载体由聚异戊二烯醇（氨基戊醇，APrens）的阳离子衍生物和 1,2-二油酰基-sn-甘油-3-磷酸乙醇胺（DOPE）组成。这些载体以前被证明对生物体无毒，现在我们测试它们是否适合给予坎地沙坦，一种降压药。自发性高血压大鼠（SHR）接受新鲜制备的载体中坎地沙坦（0.1mg/kg 体重/天；皮下注射）注射两周。大鼠的动脉血压通过遥测法测量。尿液和血液采集在代谢笼中进行。在 SHR 的另一组中，评估了单次皮下注射新制剂的药代动力学。在含有 APrens 的 DOPE 分散体中给予坎地沙坦的降压活性明显大于仅由 DOPE 组成的坎地沙坦分散体或在经典溶剂（碳酸钠）中给予的坎地沙坦。药代动力学参数清楚地表明，APren 载体中的坎地沙坦比仅在 DOPE 分散体中或在溶剂中给予的相同药物更快且浓度更高（几乎整个观察期间）进入血液。只有接受 APrens 载体中坎地沙坦的大鼠血清肌酐（P）显著降低（从 0.80±0.04 降至 0.66±0.09mg/dl；p<0.05），而其他组治疗后 P 保持不变。此外，新衍生物增加了载体的载药量，这是任何药物传递系统的一个有价值的特征。综上所述，我们的发现使我们得出结论，APrens 是潜在有价值的脂质药物载体的组成部分。
