Arthur Christine, Song Lin, Culp William, Brown Aliza, Borrelli Michael, Skinner Robert, Hendrickson Howard
Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, 72205, USA.
College of Pharmacy, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 W. Markham Street #622, Little Rock, Arkansas, 72205, USA.
AAPS J. 2017 Mar;19(2):520-526. doi: 10.1208/s12248-016-0013-0. Epub 2016 Dec 27.
IV injection of dodecafluoropentane emulsion (DDFPe) increases oxygen transportation and reduces brain infarct volume in a rabbit stroke model. Tissue distribution of the parent perfluorocarbon dodecafluoropentane (DDFP) is unknown but is critical to understanding the mechanism by which DDFPe is effective in treating ischemia and for determining safe dosing. Previous studies showed a DDFP blood half-life of <2 min yet therapeutic effects lasted >90 min after injection. We describe DDFP distribution in brain, kidney, liver, spleen, and lung following nine dosing regimens in New Zealand White (NZW) rabbits. Single and multi-dose schedules were administered to NZW rabbits (n = 27). A single DDFPe dose (0.6 ml/kg) group was sacrificed 2 min after dosing and eight multi-dose groups (4 doses of 0.3 or 0.6 ml/kg and 15 doses of 0.1, 0.3, or 0.6) were sacrificed 90 min after final injections. Tissues were flash frozen and analyzed with headspace sampling/GC-MS. DDFP brain concentration increased with increasing dose in the 15 dose groups (4.70, 8.34, and 14.3 μg/g) and indicative of linear pharmacokinetics within this dose range. The DDFP lung concentration was not reflective of increasing dose or dose frequency. The total clearance of DDFP was consistent with previous reports showing 98% of DDFP is cleared within 2 h of administration.
在兔中风模型中，静脉注射十二氟戊烷乳剂（DDFPe）可增加氧输送并减少脑梗死体积。全氟碳化合物十二氟戊烷（DDFP）母体的组织分布尚不清楚，但对于理解DDFPe治疗缺血的作用机制以及确定安全剂量至关重要。先前的研究表明，DDFP的血液半衰期小于2分钟，但注射后治疗效果持续超过90分钟。我们描述了在新西兰白兔（NZW）中采用九种给药方案后DDFP在脑、肾、肝、脾和肺中的分布情况。对NZW兔（n = 27）采用单剂量和多剂量给药方案。单剂量DDFPe组（0.6 ml/kg）在给药后2分钟处死，八个多剂量组（4剂0.3或0.6 ml/kg以及15剂0.1、0.3或0.6）在最后一次注射后90分钟处死。组织迅速冷冻，采用顶空进样/气相色谱-质谱联用仪进行分析。在15剂量组中，DDFP脑浓度随剂量增加而升高（4.70、8.34和14.3 μg/g），表明在此剂量范围内呈线性药代动力学。DDFP肺浓度与剂量增加或给药频率无关。DDFP的总清除率与先前报道一致，表明98%的DDFP在给药后2小时内清除。
