1. [Tubular transporters OAT1 and MRP2 and clearance of adefovir]
- Author
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Aude, Servais, Philippe, Lechat, Noël, Zahr, Saik, Urien, Guy, Aymard, Marie Chantal, Jaudon, Gilbert, Deray, and Corinne, Isnard Bagnis
- Subjects
Male ,Organic Anion Transport Protein 1 ,Probenecid ,Adenine ,Organophosphonates ,Animals ,Multidrug Resistance-Associated Proteins ,Rats, Wistar ,Uricosuric Agents ,Kidney ,Antiviral Agents ,Rats - 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 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 (P0.05) 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.
- Published
- 2005