Rosseels Marie-Luce A, Delaunois Annie G, Hanon Etienne, Guillaume Philippe J-P, Martin Frédéric D C, van den Dobbelsteen Diels J
Non-Clinical Safety Evaluation, UCB Pharma S.A., Chemin du Foriest, B-1420 Braine-l'Alleud, Belgium.
Regul Toxicol Pharmacol. 2013 Dec;67(3):351-9. doi: 10.1016/j.yrtph.2013.08.013. Epub 2013 Aug 23.
Hydroxypropyl-β-cyclodextrin (HPβCD) is a complexation agent used to enhance drug solubilization and formulation stability. Although its toxicity is well characterized, its cardiovascular effects are less known. To investigate them, HPβCD was infused intravenously over 10 min in anesthetized dogs (10-40% (w/v, i.e. 200-800 mg/kg) in non-denervated animals and at 40% in denervated animals). HPβCD increased renal arteriolar resistance and decreased renal blood flow at all doses, almost immediately after infusion start, more drastically in females. A less pronounced increase in total peripheral resistance occurred in females only due to sex difference in sympathetic tone. Pulmonary hemodynamic parameters remained unaffected, suggesting that the renal effect was rather selective. As a consequence of the increased systemic blood pressure, heart rate decreased in normal animals without direct effect on cardiac conductance. This effect was abolished in denervated animals. This suggests that autonomous nervous feedback loops are functional in normal animals and that HPβCD has no direct chronotropic effect. In conclusion, systemic and renal hemodynamic changes should be considered as potential background effects at 200-400 mg/kg. At higher doses (800 mg/kg), changes are more pronounced and could mask/exacerbate hemodynamic response of drug candidate; such doses should be avoided in nonclinical safety studies.
羟丙基-β-环糊精（HPβCD）是一种用于增强药物溶解性和制剂稳定性的络合剂。尽管其毒性已得到充分表征，但其对心血管的影响却鲜为人知。为了对此进行研究，在麻醉犬中于10分钟内静脉输注HPβCD（在未去神经支配的动物中为10 - 40%（w/v，即200 - 800 mg/kg），去神经支配的动物中为40%）。HPβCD在所有剂量下均增加肾小动脉阻力并降低肾血流量，几乎在输注开始后立即出现，在雌性动物中更为明显。仅由于交感神经张力的性别差异，雌性动物的总外周阻力有不太明显的增加。肺血流动力学参数未受影响，这表明肾脏效应具有相当的选择性。由于全身血压升高，正常动物的心率下降，而对心脏传导无直接影响。这种效应在去神经支配的动物中消失。这表明自主神经反馈回路在正常动物中起作用，并且HPβCD没有直接的变时效应。总之，在200 - 400 mg/kg时，全身和肾脏血流动力学变化应被视为潜在的背景效应。在更高剂量（800 mg/kg）时，变化更为明显，可能掩盖/加剧候选药物的血流动力学反应；在非临床安全性研究中应避免使用此类剂量。
