Dermal metabolism of topically applied drugs: pathways and models reconsidered.

The study of skin metabolism is of prime importance not only in the field of transdermal drug delivery but also for the safe and efficient local skin treatment with topically applied substances. Since it has become clear that even peptides may be delivered across the permeation barrier of the stratum corneum, e.g. by means of iontophoresis, phonophoresis or electroporation, the enzymatic barrier of the epidermis deserves more attention as another important limiting factor for the dermal delivery of drugs. The purpose of this review is to give a survey of the major aspects concerning the assessment of the metabolism of xenobiotics in the skin. First, this review will focus on the localization of enzyme activity within the skin. Further, important aspects to be considered for the planning and evaluation of skin metabolism studies will be discussed: differences among species and requirements of skin quality. Among the various metabolic pathways within the skin broad interest will be concentrated on the metabolism of peptide drugs. Therefore, exopeptidases in the skin are the subject of an additional section. Also models for skin metabolism studies will be especially considered including the development of suitable cell culture models. Finally, major gap areas in the investigation of skin metabolism will be identified and summarized, namely; classes of xenobiotics, proteolytic enzyme activity in the skin, validity of experimental models, localization of enzyme activity and physical model development.