Pershing L K, Lambert L, Wright E D, Shah V P, Williams R L
Department of Medicine, University of Utah School of Medicine, Salt Lake City.
Arch Dermatol. 1994 Jun;130(6):740-7. doi: 10.1001/archderm.130.6.740.
Effective topical drug therapy requires drug delivery into the skin to produce the desired pharmacodynamic response. For topical corticosteroids, the visual skin-blanching assay has been used to rank the potency of the corticosteroids and their overall efficacy. While vehicles have been shown to influence the resulting blanching response, the dose of drug applied has not always produced proportional differences in the blanching assay. The mechanism of the nonproportional pharmacodynamic response to the corticosteroid dose is unclear. We describe four methods for assessing the dose-response relationship of topical betamethasone dipropionate on the ventral forearm of six human subjects: duration, concentration, film thickness, and surface area. Drug uptake analysis in human stratum corneum and the resulting pharmacodynamic response, measured visually and with a chromameter, were performed with each method to quantify the dose-response relationship.
Only the concentration and duration methods demonstrated an increase in mean drug uptake with increasing dose. The maximal mean pharmacodynamic response reflected the mean drug uptake with all four methods. Application conditions for maximal pharmacodynamic activity of topical betamethasone dipropionate in the skin include short duration of treatment (< or = 2 hours), a lower concentration than commercially marketed, and thin film thicknesses (1 to 5 microns).
A dose response can be produced by increasing the drug concentration or the duration of application time. Achievement of steady-state betamethasone dipropionate uptake into the stratum corneum was not commensurate with the maximal pharmacodynamic response. Very small amounts of this potent corticosteroid within the skin appear to maximize the receptor response to drug.
有效的局部药物治疗需要将药物输送到皮肤中以产生所需的药效学反应。对于局部用皮质类固醇，视觉皮肤变白试验已被用于对皮质类固醇的效力及其总体疗效进行排名。虽然载体已被证明会影响产生的变白反应，但所应用药物的剂量在变白试验中并不总是产生成比例的差异。对皮质类固醇剂量的非比例药效学反应机制尚不清楚。我们描述了四种评估丙酸倍他米松在六名人类受试者前臂腹侧的剂量反应关系的方法：持续时间、浓度、薄膜厚度和表面积。使用每种方法在人角质层中进行药物摄取分析，并通过视觉和色度计测量由此产生的药效学反应，以量化剂量反应关系。
只有浓度和持续时间方法显示平均药物摄取量随剂量增加而增加。最大平均药效学反应反映了所有四种方法的平均药物摄取量。皮肤中丙酸倍他米松最大药效学活性的应用条件包括治疗持续时间短（≤2小时）、低于市售浓度以及薄膜厚度（1至5微米）。
通过增加药物浓度或应用时间的持续时间可以产生剂量反应。丙酸倍他米松在角质层中达到稳态摄取与最大药效学反应并不相称。皮肤内极少量的这种强效皮质类固醇似乎能使受体对药物的反应最大化。
