The interaction of pharmacologically active drugs with SC biochemical components is underestimated in pharmaceutical research. The aim of this research was to illustrate that some drugs intended for transdermal delivery could interact with the protein component of SC. Such interactions could be in favor of or opposition to their percutaneous absorption. IR microspectroscopy was used to delineate possible interaction of SC keratin with three losartan salts LOS-K, LOS-DEA and LOS-AML salts in addition to AML-BES salt. The results of PCA, combined with comparisons of average second derivative spectra of SC samples treated with these salts and the control SC, showed that LOS-DEA did not interact with SC, thus providing base line permeation of losartan. AML-BES, LOS-AML and LOS-K salts modified the conformational structure of keratin. The disorganization effect on the α-helical structure and induced formation of parallel β-sheets and random coils were in the order of AML-BES˃LOS-AML˃LOS-K. The order of the impact of treatments which resulted in increased formation of β-turns was AML-BES˃LOS-AML. The formation of antiparallel β-sheets was manifested by LOS-AML. Thus, the overall effect of these salts on the SC protein was AML-BES˃LOS-AML˃LOS-K. The impact of LOS-K was associated with improved permeation whereas the impact of LOS-AML was associated with hindered permeation of both losartan and amlodipine. There is a possibility that losartan and amlodipine when present in combination inside SC, their binding to the protein is enhanced leading to being retained within SC.