Percutaneous absorption of topically applied mannitol and progesterone was compared in vivo with the hairless and hairy rat. Urinary excretion and skin concentration profiles after topical application of mannitol demonstrated that hairless rat skin was a "leakier" barrier to percutaneous absorption of polar compounds than was hairy rat skin, independent of formulation. Liposomal, but not aqueous mannitol was retained in hairy rat skin (> 0.5% after 12 h), whereas only negligible amounts were retained in hairless rat skin, regardless of formulation. Progesterone absorption from hydroalcohol and liposomal formulations into hairless rat skin was about five times greater than that in hairy rat skin. Skin delipidization by acetone resulted in a dramatic reduction in the cutaneous barrier to systemic mannitol absorption, which was much more pronounced in hairy than in hairless rat skin. Histological findings of patulous cysts and enlarged, highly vascularized sebaceous glands in the hairless rat suggested that these structures may enhance polar pathways and provide a lipophilic reservoir relative to the fully developed hair follicles of the hairy rat. Collectively, the results document percutaneous absorption differences as a function of animal model, and also suggest that follicular structures make a major contribution to passive percutaneous absorption.