The localisation of primaquine was studied within epidermal membranes following the application of a topical dose. A depth profile was constructed by tape-stripping human epidermis following permeation of a 70 mgml(-1) solution of primaquine in Miglyol 840. Comparative binding studies of primaquine were carried out on isolated human stratum corneum and whole epidermis, using normal and delipidised tissue. An additional study was undertaken using bovine keratin powder as a model of human keratin. The depth profile showed that primaquine decreased with depth and decreasing keratin content, and the total primaquine recovered (15.5 mgcm(-2)) was 300 x the amount of extractable lipid. Binding to delipidised skin was saturable, whereas binding to normal skin was unsaturable, reflecting the high miscibility of drug in the lipid domains as opposed to a finite, but large number of binding sites on the corneocytes. Binding was greater for stratum corneum than stratum corneum plus viable epidermis, probably due to greater accessibility of corneocytes keratin. Binding was dose dependent, although binding to delipidised skin was far greater than to normal skin, demonstrating that primaquine had an affinity for lipoidal regions and an even higher affinity for the proteinaceous domains of the stratum corneum. This was supported by high saturable levels of primaquine binding to bovine horn keratin. The results indicated extensive binding to corneocyte keratin has a significant effect on reservoir formation and the permeability of primaquine across human skin. It is speculated that the large amount of keratin presented at the skin surface may be an evolutionary protective process for the sequestration of ingressing molecules.