title: Tubular transporters and clearance of adefovir.
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.
authors.affiliation: Nephrology Department, Pitié-Salpêtrière University Hospital, 47 Boulevard de l'Hôpital, 75013, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Servais
authors.forename: Philippe
authors.initials: P
authors.lastname: Lechat
authors.forename: Noël
authors.initials: N
authors.lastname: Zahr
authors.forename: Saik
authors.initials: S
authors.lastname: Urien
authors.forename: Guy
authors.initials: G
authors.lastname: Aymard
authors.forename: Marie Chantal
authors.initials: MC
authors.lastname: Jaudon
authors.forename: Gilbert
authors.initials: G
authors.lastname: Deray
authors.forename: Corinne
authors.initials: C
authors.lastname: Isnard Bagnis
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000225:Adenine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003306:Coproporphyrins / Q000652:urine; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D063065:Organophosphonates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011339:Probenecid / Q000097:blood / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014528:Uricosuric Agents / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D003306:Coproporphyrins; D007166:Immunosuppressive Agents; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; C421043:Slc22a6 protein, rat; D014528:Uricosuric Agents; C053001:adefovir; D000225:Adenine; D011339:Probenecid