title: Inhibition of the human organic anion transporter 1 by the caffeine metabolite 1-methylxanthine.
abstract: Caffeine (1,3,7-trimethylxanthine) is daily and widely consumed in beverages and food and is mainly metabolized to 1,7-dimethylxanthine and 1-methylxanthine. Indirect clinical evidence suggests that 1-methylxanthine interacts with the organic anion transport system in the human kidney. In this study the effect of caffeine and its main metabolites on the human organic anion transporter 1 (hOAT1) was investigated using CHO cells overexpressing hOAT1. The uptake of 6-carboxyfluorescein into CHO(hOAT) cells was significantly inhibited by > or = 100 microM of 1-methylxanthine. Five hundred micromolar 1-methylxanthine was equieffective to 100 microM probenecid. In contrast, caffeine and 1,7-dimethylxanthine did not inhibit the transport of 6-carboxyfluorescein at concentrations up to 500 microM. In conclusion, the caffeine metabolite 1-methylxanthine inhibits the transport activity of hOAT1 in vitro. The central involvement of hOAT1 in the renal excretion of numerous drugs suggests that this inhibition may alter the pharmacokinetics of a series of clinically important drugs in humans.
authors.affiliation: Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Rengelshausen
authors.forename: Heike
authors.initials: H
authors.lastname: Lindenmaier
authors.forename: Tomas
authors.initials: T
authors.lastname: Cihlar
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Walter-Sack
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
mesh_terms: D000818:Animals; D016466:CHO Cells; D002110:Caffeine / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000493:pharmacokinetics; D006801:Humans; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013806:Theophylline / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D005452:Fluoresceins; D027361:Organic Anion Transporters; D014970:Xanthines; C024098:6-carboxyfluorescein; D002110:Caffeine; C053085:1-methylxanthine; D013806:Theophylline; C021183:1,7-dimethylxanthine