Intracutaneous Distributions of Fluconazole, Itraconazole, and Griseofulvin in Guinea Pigs and Binding to Human Stratum Corneum

Abstract

We have compared the distribution of fluconazole (FLC) with that of itraconazole (ITC) and griseofulvin (GRF) in the abdominal skin tissues after a single oral dose was administered to guinea pigs. The FLC concentrations in the stratum corneum reached a peak at 2 h after administration and were similar to those of ITC and higher than those of GRF in spite of the administration of a lower dose. GRF was eliminated from the stratum corneum faster than FLC and ITC. The FLC concentrations were also remarkably higher than those of ITC and GRF in the epidermis-cutis but lower in the subcutaneous fatty tissue. The distribution characteristics of each drug result from differences in their physicochemical properties. Following the administration of multiple doses, the FLC concentrations in the stratum corneum were highest in the abdominal skin tissues; those at 24 h after each administration increased gradually and were maintained at a level more than 10 times higher than that of the plasma concentrations. The FLC concentrations in the planta pedis stratum corneum and in the nail showed good dose proportionality and obvious accumulation and were 60 and 40 times as high as that in plasma on day 14. The extent of binding of FLC to human corneous keratin in vitro was about 10%, which is lower than those of ITC (94 to 97%) and GRF (36 to 38%). FLC, unlike ITC, therefore, is presumed to exist in the stratum corneum at high concentrations in an active nonbinding form. These excellent intracutaneous pharmacokinetic properties of FLC probably account in large part for the in vivo efficacy of FLC.

Surfactant-based Transdermal System for Fluconazole Skin Delivery

“…However, this evidence was found for oral treatments [9]. Considering the topical application of the formulations studied here, it is possible to promote drug permeation or skin retention by changing only the composition of the components in the formulations.…”

“…Fluconazole was used as the drug model because it is a triazole antifungal agent with broad-spectrum activity. It is effective for deep seated mycosis caused by Candida, Cryptococcus spp., and others and also for superficial infections caused by dermatophytes such as Microsporum and Trichophyton spp [9].…”

Tissue Penetration of Antifungal Agents

“…The prolonged exposure of antifungal agents within the skin, nail, and nail bed is an important factor determining the outcome of treatment of dermatomycosis (215). Fluconazole concentrations within the dermis are similar to those in plasma (216,217), but concentrations in the stratum corneum are up to 40 times those in plasma (217,218) (Fig.…”

Disparate SAR Data of Griseofulvin Analogues for the Dermatophytes Trichophyton mentagrophytes, T. rubrum, and MDA-MB-231 Cancer Cells

“…7 Upon administration to man, griseofulvin accumulates in the skin (stratum corneum), where it presumably binds to keratin. 8 The mode of action is still not determined, but tubulin binding has been proposed. 9,10 More than 400 griseofulvin analogues have been reported since its discovery, and the activity of over 300 of these have been compared with griseofulvin (1) against six dermatophytes in a study by Crosse et al 11 The curling of hyphae in Botrytis allii were also tested, but this phenotype did not correlate with the growth inhibitory effect of the analogues.…”

“…Comparing the two fungal SARs with the anticancer cytotoxicity SAR afforded distinct differences. The analogues 8, 25, 27, and 38 were inactive or had low potency against both fungi but either retained the activity (8) or were at least 2-fold more active against the cancer cells compared to 1. The 2′-benzyloxy analogue (17) was less active against both fungi in this study and against six dermatophytes in the study by Crosse et al 11 This analogue is however nine times more potent than 1 against the cancer cell line MDA-MB-231.…”