The dose-duration effect on cutaneous pharmacokinetics of metronidazole from topical dermatological formulations in Yucatan mini-pigs

Abstract

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.

Keywords: Bioavailability; Cutaneous pharmacokinetics; Dermal microdialysis; Flip-flop pharmacokinetics; Metronidazole; Topical dermatological drug products.