High keratin binding and slow desorption kinetics are assumed to be responsible for the formation of the stratum corneum (SC) reservoir. We measured equilibrium binding coefficients (K(b)) and desorption rate constants (k(off)) with bovine hoof/horn keratin and six solutes with similar molecular weight (180-288 Da) and varying lipophilicities [expressed as octanol-water distribution coefficient, i.e., a partition coefficient corrected for pH (log K(pH))-0.13 to 3.8]. Two ionizable solutes within this set were tested at different pH values as degree of ionization and lipophilicity were expected to influence equilibrium binding and desorption kinetics. The unbound fraction at equilibrium varied between 18% and 93%. All solutes exhibited linear binding isotherms within the investigated concentration range. Equilibrium binding and the rate of desorption are both functions of solute lipophilicity [log K(b) = 1.23 + 0.32 log K(pH); log k(off) = 1/(25.75 + 8.35 K(pH) (0.34))]. Our results prove that slow desorption from keratin may be a major contributor to the SC reservoir. Also, they prove that reservoir formation is relevant for lipophilic solutes independent of drug class, thus allowing new options for topical pharmacotherapy.