Tubular transporters and clearance of adefovir

Adefovir is transported by the organic anion transporter (OAT1) and the multidrug resistant protein (MRP2, 4 and 5). We studied adefovir clearance in rat after inhibition of transporters by probenecid and in mutant transport-deficient (TR−) rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population nonlinear mixed effect modeling. The fraction of drug excreted in the urine was low. Renal clearance of adefovir was significantly lower ( P < 0.05) in probenecid TR− rats (0.03 ± 0.02 l/h) than in normal control (0.09 ± 0.05 l/h), in normal probenecid (0.10 ± 0.07 l/h) and in TR− control rats (0.13 ± 0.07 l/h). In vivo in rats MRP2 mutation alone did not affect adefovir clearance suggesting that MRP2 does not play a critical role in the secretion of adefovir. Additional pharmacological inhibition of transporters decreased renal clearance, which may reflect inhibition of compensating transport mechanisms activated when MRP2 is lacking.