Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, Brooklyn, NY, USA.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
Eur J Pharm Biopharm. 2022 Jun;175:43-52. doi: 10.1016/j.ejpb.2022.05.001. Epub 2022 May 5.
Dermal microdialysis (dMD) permits the investigation of cutaneous pharmacokinetics (cPK) for topical dermatological drug products (TDDP). dMD involves probe implantation into the dermis and a sample collection system that restricts subjects' movements for the experimental duration. A truncated dose-duration, by TDDP removal at predetermined time-points, may help to adequately characterize the cPK in a relatively short time. The goals of this study were to: assess and compare the dose-duration effect on the dermal exposure of metronidazole (MTZ) containing TDDPs; and characterize MTZ dermal elimination following TDDP application and direct dermal delivery of MTZ utilizing a retrodialysis/microdialysis approach that we termed "dermal infusion." MTZ cream and gel were applied on three Yucatan mini-pigs for dose-durations of 6-hr, 12-hr, or 48-hr. The gel's dermal exposure was similar among the three dose-durations. Conversely, at the 6-hr dose-duration, the cream's dermal exposure was significantly lower than other cream dose-durations while also comparable to the gel. In comparison, the 12-hr and 48-hr cream exposures were not significantly different. Terminal-phase half-live differences between the MTZ TDDP's and dermal-infusion indicate flip/flop cPK. Truncating topical dose-duration may provide a valuable strategy to reduce experimental duration; however, dose-duration must be carefully selected if the goal is to discriminate between formulations.
皮肤微透析（dMD）允许对局部皮肤科药物产品（TDDP）进行皮肤药代动力学（cPK）的研究。dMD 涉及将探针植入真皮和样品采集系统，该系统限制了受检者在实验期间的活动。通过在预定时间点去除 TDDP 来缩短剂量-持续时间，可以帮助在相对较短的时间内充分描述 cPK。本研究的目的是：评估和比较剂量-持续时间对包含 MTZ 的 TDDP 的皮肤暴露的影响；并利用我们称为“皮肤输注”的逆行透析/微透析方法来描述 TDDP 应用和 MTZ 直接皮肤给药后 MTZ 的皮肤消除情况。将 MTZ 霜和凝胶应用于三只尤卡坦迷你猪，剂量持续时间为 6 小时、12 小时或 48 小时。三种剂量持续时间下，凝胶的皮肤暴露情况相似。相反，在 6 小时剂量持续时间下，乳膏的皮肤暴露明显低于其他乳膏剂量持续时间，同时也与凝胶相当。相比之下，12 小时和 48 小时的乳膏暴露没有显著差异。MTZ TDDP 和皮肤输注之间的终末相半衰期差异表明 cPK 翻转。缩短局部剂量持续时间可能是减少实验持续时间的一种有价值的策略；但是，如果目标是区分配方，则必须仔细选择剂量持续时间。
