Wester R C, Melendres J, Sedik L, Maibach H I
Department of Dermatology, University of California, San Francisco.
J Pharm Sci. 1994 Feb;83(2):124-5. doi: 10.1002/jps.2600830203.
Azone (1-dodecylazacycloheptan-2-one) is an agent that has been shown to enhance percutaneous absorption of drugs. Azone is thought to act by partitioning into skin lipid bilayers and thereby disrupting the structure. An open-label study was done with nine volunteers (two males, seven females; aged 51-76 years) in which Azone cream (1.6%; 100 mg) was topically dosed on a 5 x 10-cm area of the ventral forearm for 21 consecutive days. On days 1, 8, and 15, the Azone cream contained 47 microCi of [14C]Azone. The skin application site was washed with soap and water after each 24-h dosing. Percutaneous absorption was determined by urinary radioactivity excretion. The [14C]Azone was ring labeled [14C-2-cyclo-heptan]. Radiochemical purity was > 98.6% and cold Azone purity was 99%. Percutaneous absorption of the first dose (day 1) was 1.84 +/- 1.56% (SD) of applied dose for 24-h skin application time. Day 8 percutaneous absorption, after repeated application, increased significantly (p < 0.002) to 2.76 +/- 1.91%. Day 15 percutaneous absorption, after continued repeated application, stayed the same at 2.72 +/- 1.21%. In humans, repeated application of Azone results in an initial self-absorption enhancement, probably due to its mechanism of action. However, steady-state percutaneous absorption of Azone is established after this initial change. Thus, Azone can enhance its own absorption as well as that of other compounds. This should be considered relevant for any pharmacological or toxicological evaluation. Washing the skin site of application with soap and water only recovered 1-2% of applied radioactivity. Previous published studies recovered the Azone dose with ethanol washes. Thus, there could potentially be an accumulation of Azone in skin.
氮酮（1-十二烷基氮杂环庚烷-2-酮）是一种已被证明能增强药物经皮吸收的制剂。氮酮被认为是通过分配进入皮肤脂质双层从而破坏其结构来发挥作用的。对9名志愿者（2名男性，7名女性；年龄51 - 76岁）进行了一项开放标签研究，将含1.6%（100毫克）氮酮的乳膏连续21天局部涂抹于前臂腹侧5×10厘米的区域。在第1天、第8天和第15天，氮酮乳膏含有47微居里的[¹⁴C]氮酮。每次给药24小时后，用肥皂和水清洗皮肤涂抹部位。通过尿放射性排泄来测定经皮吸收情况。[¹⁴C]氮酮是环标记的[¹⁴C-2-环庚烷]。放射化学纯度>98.6%，非放射性氮酮纯度为99%。首次给药（第1天）在24小时皮肤涂抹时间内的经皮吸收量为给药剂量的1.84±1.56%（标准差）。重复给药后，第8天的经皮吸收量显著增加（p<0.002），达到2.76±1.91%。持续重复给药后，第15天的经皮吸收量保持不变，为2.72±1.21%。在人体中，重复应用氮酮会导致最初的自身吸收增强，这可能归因于其作用机制。然而，在这一初始变化之后会建立氮酮的稳态经皮吸收。因此，氮酮既能增强自身的吸收，也能增强其他化合物的吸收。在任何药理学或毒理学评估中都应考虑到这一点。仅用肥皂和水清洗皮肤涂抹部位仅回收了1 - 2%的给药放射性。先前发表的研究用乙醇清洗回收了氮酮剂量。因此，氮酮在皮肤中可能存在潜在的蓄积。
