体内绵羊模型中丁丙诺啡和去甲丁丙诺啡的脑药代动力学比较。

Comparison of cerebral pharmacokinetics of buprenorphine and norbuprenorphine in an in vivo sheep model.

作者信息

Jensen M L, Foster D, Upton R, Grant C, Martinez A, Somogyi A

机构信息

Department of Pharmacology and Pharmacotherapy, University of Copenhagen, Denmark.

出版信息

Xenobiotica. 2007 Apr;37(4):441-57. doi: 10.1080/00498250701251126.

DOI:10.1080/00498250701251126

PMID:17455115

Abstract

The pharmacokinetics and time course of blood-brain equilibration of buprenorphine (BUP) and norbuprenorphine (norBUP) in sheep were characterized. Sheep were administered 0.04 mg kg(-1) BUP or 0.6 mg kg(-1) norBUP as 4-min i.v. infusions. The cerebral kinetics were inferred from arterio-sagittal sinus concentration gradients and changes in cerebral blood flow. These data were fitted to physiologically based pharmacokinetic models. BUP cerebral kinetics were best described by a membrane-limited model with a large equilibration delay (half-life of 20 min) between brain and blood due to intermediate permeability (47 ml min(-1)) and a large cerebral distribution volume (595 ml). Significant limitation in permeability (6 ml min(-1)) characterized the cerebral kinetics of norBUP with a cerebral distribution volume (157 ml) giving a blood-brain equilibration half-life (21 min) similar to that for BUP. The logD of BUP and norBUP were 3.93 +/- 0.08 and 1.18 +/- 0.04 (mean +/- SD), respectively. Both compounds revealed slow cerebral equilibration with variations in degree of permeability and distribution volume reflecting the difference in lipophilicity. It is possible that norBUP contributes to the central effects seen after chronic BUP administration as this study demonstrated its entry into the brain.

摘要

对绵羊体内丁丙诺啡（BUP）和去甲丁丙诺啡（norBUP）的药代动力学及血脑平衡的时间进程进行了表征。给绵羊静脉注射0.04 mg kg⁻¹的BUP或0.6 mg kg⁻¹的norBUP，输注时间为4分钟。通过动脉-矢状窦浓度梯度和脑血流量的变化推断脑动力学。这些数据被拟合到基于生理的药代动力学模型中。BUP的脑动力学最好用膜限制模型来描述，由于中等通透性（47 ml min⁻¹）和较大的脑分布容积（595 ml），脑与血之间存在较大的平衡延迟（半衰期为20分钟）。norBUP的脑动力学特征是通透性显著受限（6 ml min⁻¹），脑分布容积（157 ml）使其血脑平衡半衰期（21分钟）与BUP相似。BUP和norBUP的logD分别为3.93±0.08和1.18±0.04（平均值±标准差）。两种化合物均显示出缓慢的脑平衡，通透性和分布容积的变化反映了亲脂性的差异。由于本研究证明norBUP可进入脑内，因此它可能导致长期服用BUP后出现的中枢效应。