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

Biochim Biophys Acta. 2005 Aug 15;1714(2):85-92. doi: 10.1016/j.bbamem.2005.06.006.


It is well known that human organic anion transporter 1 (hOAT1) transports many kinds of drugs, endogenous 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 derivative>7-methyl derivative>3-methyl derivative falling dotsxanthine>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.

MeSH terms

  • Animals
  • Biological Transport
  • CHO Cells
  • Caffeine / chemistry
  • Caffeine / pharmacology
  • Cricetinae
  • Cricetulus
  • Humans
  • Molecular Structure
  • Organic Anion Transport Protein 1 / antagonists & inhibitors*
  • Organic Anion Transport Protein 1 / metabolism
  • Theobromine / chemistry
  • Theobromine / pharmacology
  • Theophylline / chemistry
  • Theophylline / pharmacology
  • Uric Acid / chemistry
  • Uric Acid / pharmacology
  • Xanthines / chemistry*
  • Xanthines / pharmacology*
  • p-Aminohippuric Acid / metabolism


  • Organic Anion Transport Protein 1
  • Xanthines
  • Uric Acid
  • Caffeine
  • Theophylline
  • Theobromine
  • p-Aminohippuric Acid