title: Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir.
abstract: Acyclic nucleotide phosphonates (adefovir, cidofovir, and tenofovir) are eliminated predominantly into the urine, and renal failure is their dose-limiting toxicity, particularly for adefovir and cidofovir. In this study, we examined the involvement of multidrug resistance-associated protein (MRP)4 (ABCC4) in their luminal efflux in the kidney. ATP-dependent uptake of adefovir and tenofovir but not cidofovir was observed only in the membrane vesicles expressing MRP4. The ATP-dependent uptake of adefovir and tenofovir by MRP4 was not saturated at 1 mM. The ATP-dependent uptake of adefovir by membrane vesicles expressing MRP4 was osmotic-sensitive. No ATP-dependent uptake of either agent was observed in the membrane vesicles expressing human MRP2 or breast cancer resistance protein. These nucleotide analogs were given to mice by constant intravenous infusion, and the plasma, urine, and tissue concentrations were determined. The kidney accumulation of adefovir and tenofovir was significantly greater in Mrp4 knockout mice (130 versus 66 and 191 versus 87 pmol/g tissue, respectively); thus, the renal luminal efflux clearance was estimated to be 37 and 46%, respectively, of the control. There was no difference in the fraction of mono- and diphosphorylated forms of adefovir in the kidney between wild-type and Mrp4 knockout mice. In mice, cidofovir was also eliminated via the urine by tubular secretion as well as glomerular filtration. There was no change in the kinetic parameters of cidofovir in Mrp4 knockout mice. Our results suggest that MRP4 is involved in the luminal efflux of both adefovir and tenofovir, but it makes only a limited contribution to the urinary excretion of cidofovir.
authors.affiliation: Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Japan, and Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Imaoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Masashi
authors.initials: M
authors.lastname: Adachi
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.forename: Kenji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000652:urine; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000652:urine; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007668:Kidney / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000502:physiology*; D063065:Organophosphonates / Q000493:pharmacokinetics* / Q000652:urine; D009995:Osmosis; D051437:Renal Insufficiency / Q000139:chemically induced; D000068698:Tenofovir; D014018:Tissue Distribution
chemical_list: D000225:Adenine; D000255:Adenosine Triphosphate; D000998:Antiviral Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D063065:Organophosphonates; D000068698:Tenofovir; C000715087:ABCC2 protein, human; C489540:Abcc4 protein, mouse; C053001:adefovir