Ishikawa T, Dhawan V, Chaly T, Robeson W, Belakhlef A, Mandel F, Dahl R, Margouleff C, Eidelberg D
Department of Neurology, North Shore University Hospital/Cornell, University Medical College, Manhasset, New York 11030, USA.
J Cereb Blood Flow Metab. 1996 Sep;16(5):854-63. doi: 10.1097/00004647-199609000-00010.
Flurodopa (FDOPA) is an analogue of L-di-hydroxyphenylalanine (L-dopa) used to assess the nigrostriatal dopamine system in vivo with positron emission tomography (PET). However, FDOPA/PET quantitation is complicated by the presence of the 3-O-methyl-FDOPA (3OMFD) fraction in brain and plasma. Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake. We performed FDOPA/PET with and without the OR-611 preadministration in six Parkinson's disease (PD) patients. We measured the time-course of the plasma FDOPA and 3OMFD fractions using high-pressure liquid chromatography (HPLC). We calculated striato-occipital ratios (SOR), and estimated the striatal FDOPA uptake rate constant graphically using the plasma FDOPA and occipital tissue time activity curves (KiFD and KiOCC, respectively). We also estimated striatal dopa decarboxylase (DDC) activity (k3D) using a model incorporating independent measurements of 3OMFD transport kinetic rate constants. With the preadministration of OR-611, the pharmacological efficiency in plasma was prolonged significantly (21.1-37.7%; p < 0.01). We also observed significant mean elevations in SOR and KiOCC by 21.8 and 53.5%, respectively (p < 0.05). KiFD and k3D did not show significant change. We conclude that OR-611 prolongs the circulation time of FDOPA in the plasma but does not alter rate constants for striatal FDOPA uptake or decarboxylation.
氟多巴(FDOPA)是左旋二羟基苯丙氨酸(L-多巴)的类似物,用于通过正电子发射断层扫描(PET)在体内评估黑质纹状体多巴胺系统。然而,脑和血浆中3-O-甲基-FDOPA(3OMFD)部分的存在使FDOPA/PET定量变得复杂。外周儿茶酚-O-甲基转移酶(COMT)抑制剂恩他卡朋(OR-611)预处理可大大降低血浆中3OMFD部分,并为评估血浆3OMFD部分在几种FDOPA摄取动力学模型中的作用提供了理想情况。我们对6例帕金森病(PD)患者进行了有无OR-611预给药的FDOPA/PET检查。我们使用高压液相色谱(HPLC)测量了血浆中FDOPA和3OMFD部分的时间进程。我们计算了纹状体-枕叶比值(SOR),并使用血浆FDOPA和枕叶组织时间-活性曲线(分别为KiFD和KiOCC)以图形方式估计纹状体FDOPA摄取速率常数。我们还使用结合3OMFD转运动力学速率常数独立测量的模型估计纹状体多巴脱羧酶(DDC)活性(k3D)。预给予OR-611后,血浆中的药理效率显著延长(21.1-37.7%;p<0.01)。我们还观察到SOR和KiOCC分别显著平均升高21.8%和53.5%(p<0.05)。KiFD和k3D没有显示出显著变化。我们得出结论,OR-611延长了FDOPA在血浆中的循环时间,但不会改变纹状体FDOPA摄取或脱羧的速率常数。