Permeability Characteristics of Temozolomide and its Ester and Amide Products Through Rat and Human Skin.

Abstract

Temozolomide has been shown to possess excellent activity against malignant melanoma (skin cancer) in phase II and III clinical trials. Temozolomide is administered orally. However, for the treatment of skin disorders, delivery of this agent directly to the skin would be advantageous. The permeability characteristics of temozolomide and its lipophilic derivatives, which may have greater skin permeability, were therefore investigated. New lipophilic ester and amide derivatives were synthesised using Pybrop® and DMAP as coupling agents. In vitro permeation studies of temozolomide and its synthesised derivatives were performed on silicone membrane, full-thickness rat skin, and whole epidermis from human skin. The cumulative amounts permeated (%) of such agents were determined using HPLC. The hexyl ester derivative was the most effective in increasing the permeation of temozolomide through rat and human skin (6-10 fold higher than parent drug). This derivative is therefore a promising product which could be used to test an in vivo system. This study indicates that attachment of a hydrocarbon chain to temozolomide to increase lipophilicity also increased skin permeation (up to the hexyl derivative). Skin metabolism of temozolomide esters was also found via viable rat and human skin. Ester prodrugs were completely hydrolysed by esterase enzymes within the skin, and generated temozolomide acids, which has been shown to exhibit similar cytotoxity to temozolomide free drug.