van der Geest R, van Laar T, Gubbens-Stibbe J M, Boddé H E, Danhof M
Division of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Pharm Res. 1997 Dec;14(12):1804-10. doi: 10.1023/a:1012152401715.
Transdermal transport rates of the dopamine agonist R-apomorphine were determined in patients with idiopathic Parkinson's disease (IPD). Apomorphine was applied by iontophoresis at two current densities.
In ten patients apomorphine was applied passively for one hour. Thereafter, in the first five patients, a current density of 250 microA.cm-2 was applied for one hour and a current density of 375 microA.cm-2 in the second group. The individual pharmacokinetic parameters were obtained separately following a 15-minute zero-order intravenous infusion of 30 micrograms.kg-1. Skin resistance was measured during current delivery. Current-induced irritation was measured by Laser Doppler Flowmetry (LDF). The pharmacodynamics were quantified by a unilateral tapping score. Qualitative clinical improvements (decreased tremor, rigidity or cramp) were also recorded.
In all patients increasing plasma concentrations of R-apomorphine were found during the interval of current application. The maximum concentrations that were attained were related to the applied current density: 1.3 +/- 0.6 ng.ml-1 at 250 microA.cm-2 and 2.5 +/- 0.7 ng.ml-1 at 375 microA.cm-2. When the current was switched off all concentrations returned to baseline values in about 90 minutes. By mathematical deconvolution of the profiles it was shown that steady-state fluxes were reached within the one-hour interval of current driven transport Steady-state fluxes were calculated to be 69 +/- 30 nmol.cm-2.h-1 at 250 microA.cm-2 and 114 +/- 34 nmol.cm-2.h-1 at 375 microA.cm-2. Individual drug input rates were inversely related to the overall resistance. Significantly elevated LDF values were found after patch removal, indicating mild current induced erythema. Only subtherapeutic plasma concentrations were obtained in all patients except for one.
The results show that current-dependent delivery of apomorphine is possible in vivo at acceptable levels of skin irritation. Excellent correlation was found between the calculated in vivo transport rates and the rates that were previously obtained in vitro.
测定特发性帕金森病（IPD）患者中多巴胺激动剂R-阿扑吗啡的经皮转运速率。阿扑吗啡通过离子电渗法以两种电流密度进行给药。
对10例患者被动给予阿扑吗啡1小时。此后，在前5例患者中，施加250 μA·cm⁻²的电流密度1小时，在第二组中施加375 μA·cm⁻²的电流密度。在30 μg·kg⁻¹的零级静脉输注15分钟后分别获得个体药代动力学参数。在电流传输过程中测量皮肤电阻。通过激光多普勒血流仪（LDF）测量电流诱导的刺激。通过单侧轻敲评分对药效学进行量化。还记录了定性的临床改善情况（震颤、强直或痉挛减轻）。
在所有患者中，在施加电流的时间段内发现R-阿扑吗啡的血浆浓度升高。达到的最大浓度与施加的电流密度相关：250 μA·cm⁻²时为1.3±0.6 ng·ml⁻¹，375 μA·cm⁻²时为2.5±0.7 ng·ml⁻¹。当电流关闭时，所有浓度在约90分钟内恢复到基线值。通过对曲线进行数学反卷积表明，在电流驱动转运的1小时内达到了稳态通量。计算得出250 μA·cm⁻²时的稳态通量为69±30 nmol·cm⁻²·h⁻¹，375 μA·cm⁻²时为114±34 nmol·cm⁻²·h⁻¹。个体药物输入速率与总电阻呈负相关。去除贴片后发现LDF值显著升高，表明有轻度电流诱导的红斑。除1例患者外，所有患者均仅获得亚治疗性血浆浓度。
结果表明，在可接受的皮肤刺激水平下，阿扑吗啡的电流依赖性给药在体内是可行的。计算得出的体内转运速率与先前在体外获得的速率之间存在极好的相关性。
