[Tubular transporters OAT1 and MRP2 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 TR- rats, in which MRP2 is lacking. After treatment by probenecid or placebo, pharmacokinetics of adefovir 10 mg/kg was studied via population modeling (NONMEM). 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/hour) than in normal control (0.09 +/- 0.05 l/hour), in normal probenecid (0.10 +/- 0.07 l/hour) and in TR- control rats (0.13 +/- 0.07 l/hour). 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.
Servais
Aude
A
Service de néphrologie, CHU Pitié-Salpétrière, Paris, France. aude.servais@nck.ap-hop-paris.fr
Lechat
Philippe
P
Zahr
Noël
N
Urien
Saik
S
Aymard
Guy
G
Jaudon
Marie Chantal
MC
Deray
Gilbert
G
Isnard Bagnis
Corinne
C
D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000652:urine; D007668:Kidney / Q000378:metabolism*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors; D063065:Organophosphonates / Q000493:pharmacokinetics* / Q000652:urine; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014528:Uricosuric Agents / Q000494:pharmacology
D000225:Adenine; D000998:Antiviral Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027362:Organic Anion Transport Protein 1; D063065:Organophosphonates; D011339:Probenecid; D014528:Uricosuric Agents; C053001:adefovir