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Received for publication June 22, 2006.
Revised November 11, 2006.
Accepted for publication November 15, 2006.
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 MRP4 (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 BCRP. 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/gram tissue), respectively), and 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 di-phosphorylated 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.
Key words:
Nucleoside/Nucleotide, Organic anion
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