Received for publication April 17, 2008.
Revised May 30, 2008.
Accepted for publication June 3, 2008.

Binding of pimecrolimus and tacrolimus to skin and plasma proteins: Implications for systemic exposure after topical application

Abstract

Pimecrolimus and tacrolimus are calcineurin inhibitors used for the topical treatment of atopic dermatitis. While structurally similar, they display specific differences including higher lipophilicity and lower skin permeation of pimecrolimus. The present study aimed at understanding the reason for the differences in skin permeation; in addition, plasma protein binding of the two drugs was analyzed side by side as a basis for comparison of systemic exposure to free drug. Permeation of pimecrolimus and tacrolimus through a silicon membrane was found to be similar, therefore we assumed that differences in skin permeation could be caused by differences in affinity to skin components. To test this hypothesis, we investigated binding of pimecrolimus and tacrolimus to a preparation of soluble human skin proteins. One binding protein of approximately 15 kDa, likely corresponding to macrophilin12, displayed a similar binding capacity for pimecrolimus and tacrolimus. However, less specific, non-saturating binding to other proteins was approximately 3-fold higher for pimecrolimus. Due to the high local drug concentration following topical administration, the unspecific, high-capacity binding is likely dominating the permeation through skin. In plasma both drugs bound predominantly to lipoproteins. This may impact disposition different to albumin binding. The unbound fraction of pimecrolimus in human plasma was about 9-fold lower compared to tacrolimus (0.4±0.1% versus 3.7±0.8%). In conclusion these results provide an explanation for the observed lower systemic exposure to pimecrolimus compared to tacrolimus after topical application and suggest that differences in systemic exposure to free drug might be even more pronounced.

Key words: permeability, protein binding