Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 540, Issue 1-3, Pages 168-174Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2006.04.047
Keywords
organic anion transporter; probenecid; TR- rat; adefovir clearance
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Adefovir is transported by the organic anion transporter (OAT I) 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 10mg/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 +/- 0.021/h) than in normal control (0.09 +/- 0.051/h), in normal probenecid (0.10 +/- 0.071/b) and in TR- control rats (0.13 +/- 0.071/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. (c) 2006 Elsevier B.V. All rights reserved.
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