Tubular transporters and clearance of adefovir

Eur J Pharmacol. 2006 Jul 1;540(1-3):168-74. doi: 10.1016/j.ejphar.2006.04.047. Epub 2006 May 6.

Abstract

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 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+/-0.02l/h) than in normal control (0.09+/-0.05l/h), in normal probenecid (0.10+/-0.07l/h) and in TR- control rats (0.13+/-0.07l/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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / physiology*
  • Adenine / analogs & derivatives*
  • Adenine / blood
  • Adenine / pharmacokinetics
  • Adenine / urine
  • Animals
  • Biological Transport / drug effects
  • Biological Transport / physiology
  • Chromatography, High Pressure Liquid
  • Coproporphyrins / urine
  • Immunosuppressive Agents / blood
  • Immunosuppressive Agents / pharmacokinetics
  • Immunosuppressive Agents / urine
  • Kidney Tubules / drug effects
  • Kidney Tubules / metabolism*
  • Male
  • Metabolic Clearance Rate / drug effects
  • Models, Biological
  • Mutation / genetics
  • Organic Anion Transport Protein 1 / antagonists & inhibitors
  • Organic Anion Transport Protein 1 / physiology*
  • Organophosphonates / blood
  • Organophosphonates / pharmacokinetics*
  • Organophosphonates / urine
  • Probenecid / blood
  • Probenecid / pharmacology
  • Rats
  • Rats, Wistar
  • Time Factors
  • Uricosuric Agents / pharmacology

Substances

  • ATP-Binding Cassette Transporters
  • Abcc2 protein, rat
  • Coproporphyrins
  • Immunosuppressive Agents
  • Organic Anion Transport Protein 1
  • Organophosphonates
  • Slc22a6 protein, rat
  • Uricosuric Agents
  • adefovir
  • Adenine
  • Probenecid