Structure-affinity relationship in the interactions of human organic anion transporter 1 with caffeine, theophylline, theobromine and their metabolites

It is well known that human organic anion transporter 1 (hOAT1) transports many kinds of drugs, endogetious compounds, and toxins. However, little is known about the structure-affinity relationship. The aim of this study was to elucidate the structure-affinity relationship using a series of structurally related compounds that interact with hOAT1 Inhibitory effects of xanthine-and uric acid-related compounds on the transport of p-aminohippuric acid were examined using CHO-K1 cells stably expressing hOAT1 The order of potency for the inhibitory effects of xanthine-related compounds on PAH uptake was 1-methyl defivative > 7-methyl derivative > 3-methyl derivative(.)=(.) xanthine > 1,3,7-trimethyl derivative (caffeine). The order of potency of the inhibition was 1,3,7-trimethyluric acid > 1,3-dimethyluric acid > 1,7-dimethyluric acid > 1-methyluric acid > uric acid. A significant correlation between inhibitory potency and lipophilicity of the tested uric acid-related compounds was observed. The main determinant of the affinity of xanthine-related compounds is the position of the methyl group. On the other hand, lipophilicity is the main determinant of the affinity of uric acid-related compounds. (c) 2005 Elsevier B.V All rights reserved.