Lundin S, Svedman P, Höglund P, Jönsson K, Broeders A, Melin P
Department of Clinical Pharmacology, Lund University Hospital, Sweden.
Pharm Res. 1995 Dec;12(12):2024-9. doi: 10.1023/a:1016272729556.
Transdermal administration of the peptides [Mpa1, D-Tyr (Ethyl)2, Thr4, Orn8]-oxytocin (antocin) and [Mpa1, D-Arg8]-vasopressin (dDAVP) was studied in healthy volunteers.
A standardized skin erosion was formed preliminary by suctioning. The peptides were administered in plastic reservoirs through a 5 mm erosion and the absorption was followed for a six-day period with plasma concentration determinations on days 1, 3 and 6 with refilling the reservoirs daily with 15 microns and 10 mM solutions of dDAVP and antocin, respectively. Fourteen healthy non-smoking volunteers divided equally between the sexes, participated in the study. Plasma concentrations were measured using specific radioimmunoassays. Reservoir concentrations and metabolic stability of the peptides were determined using reverse-phase HPLC.
Both antocin and dDAVP were absorbed across the skin erosion. The absorption pattern was biphasic with a high initial absorption during days 1 and 2 followed by a lower absorption on days 3 and 6. The absorption on day 1, which was estimated at more than 50% for both peptides during a 24 h period, corresponded to a simultaneous decrease in peptide concentration in the reservoirs. The extent of absorption for antocin on days 3 and 6 was 1/3 to 1/6, respectively, of that observed on day 1. Antocin was minimally degraded in the skin reservoir while dDAVP was intact. However, accumulation of cellular material appeared in the antocin reservoirs. The absorption of antocin was reduced by exposure to intact skin surrounding the skin erosion. No pain was experienced and no scar formation was observed.
The observed biphasic absorption may be a consequence of the mild inflammatory response occurring subsequent to eroding the skin. The standardized skin erosion may provide a route for the short-term delivery of otherwise poorly absorbable peptide and protein drugs.
在健康志愿者中研究肽类物质[Mpa1, D-Tyr (Ethyl)2, Thr4, Orn8]-催产素（安托辛）和[Mpa1, D-Arg8]-加压素（dDAVP）的经皮给药情况。
通过抽吸预先形成标准化的皮肤糜烂。将肽类物质置于塑料储库中，通过5毫米的糜烂处给药，并在6天内进行吸收跟踪，分别在第1、3和6天测定血浆浓度，每天分别用15微米和10毫摩尔的dDAVP和安托辛溶液重新填充储库。14名健康的非吸烟志愿者，男女各半，参与了该研究。使用特异性放射免疫分析法测量血浆浓度。使用反相高效液相色谱法测定肽类物质的储库浓度和代谢稳定性。
安托辛和dDAVP均通过皮肤糜烂处被吸收。吸收模式为双相，在第1天和第2天有较高的初始吸收，随后在第3天和第6天吸收较低。第1天的吸收情况，估计两种肽在24小时内均超过50%，这与储库中肽浓度的同时下降相对应。安托辛在第3天和第6天的吸收程度分别为第1天观察到的吸收程度的1/3至1/6。安托辛在皮肤储库中降解极少，而dDAVP保持完整。然而，在安托辛储库中出现了细胞物质的积累。暴露于皮肤糜烂周围的完整皮肤会降低安托辛的吸收。未出现疼痛，也未观察到瘢痕形成。
观察到的双相吸收可能是皮肤糜烂后发生的轻度炎症反应的结果。标准化的皮肤糜烂可为其他难以吸收的肽类和蛋白质药物提供短期给药途径。
