Evaluation of local bioavailability of metronidazole from topical formulations using dermal microdialysis: Preliminary study in a Yucatan mini-pig model

Dermal microdialysis (dMD) can measure the rate and extent to which a topically administered active pharmaceutical ingredient (API) becomes available in the dermis. Using multiple test-sites on the same subject, and replicate probes at each test-site, it is feasible to compare the cutaneous pharmacokinetics of an API from different topical dermatological drug products in parallel on the same subject with this technique. This study design would help to reduce variability. However, there are technical considerations related to the dMD experimental methods that must be characterized and optimized to ensure that an in vivo dMD study is selective, sensitive, discriminating, and reproducible. The goals of this study were to assess: the minimum distance required between test-sites to prevent cross-talk between probes due to potential lateral-diffusion; the sensitivity of the dMD method to detect differences in the local concentration of metronidazole (MTZ) among single escalating doses; the ability to discriminate between the two different formulations; and the stability of the dMDprobes over 48 h. Results indicate that lateral-diffusion and systemic redistribution of the API following topical application of the drug product were negligible, thus MTZ measured by dMD can be selectively attributed to the dermal bioavailability of the API from the applied topical dose. The dMD methodology was able to detect differences in the bioavailability of MTZ from the cream compared to the gel when applied at the same dose, as well as among different doses of the same formulation over a 48-hour sampling duration; therefore, the method is sensitive. The percentage loss of D3-MTZ from the probe compared to its original concentration in the perfusate indicates that the probe performance was stable over the 48 h.

Automated summary

Dermal microdialysis (dMD) can accurately measure the availability of a topically administered active pharmaceutical ingredient (API) in the dermis. The study aimed to assess the dMD methodology in terms of sensitivity, discriminative ability, and reproducibility, showing that it is selective, sensitive, and stable over a 48-hour period.