OAT1 and OAT3: targets of drug-drug interaction between entecavir and JBP485

Eur J Pharm Sci. 2013 Mar 12;48(4-5):650-7. doi: 10.1016/j.ejps.2012.12.024. Epub 2013 Jan 9.


Entecavir and JBP485 (a dipeptide) exhibit the antihepatitis activities and it is possible for the two drugs to be coadministered in the treatment of hepatitis. We aimed to elucidate whether entecavir was a substrate of OAT1, OAT3, OCT, and PEPT1 and to investigate the targets of drug-drug interactions between entecavir and JBP485. Plasma and urine concentrations of entecavir following intravenous and oral administration in vivo, uptake of entecavir in kidney slices and transfected cells in vitro, were determined by LC-MS/MS. Following intravenous co-administration of entecavir and JBP485 in rats, entecavir AUC increased 1.93-fold, t1/2β was prolonged 2.08-fold, CLP decreased 49%, CLR decreased 73%, and accumulated urinary excretion decreased 54%. However, following oral co-administration, the entecavir Tmax and Cmax were not affected; the degree of change in other pharmacokinetic parameters (AUC, t1/2β, CLP, and accumulated urinary excretion) was similar to that of intravenous administration. The uptake of entecavir was nearly identical in hPEPT1- as in vector-HELA cells. In rat kidney slices, uptake of entecavir was markedly inhibited by p-aminohippurate, benzylpenicillin, JBP485, and tetraethyl ammonium. In hOAT1- and hOAT3-HEK293 cells, uptake of entecavir was significantly higher compared to vector-HEK293 cells and was markedly inhibited by p-aminohippurate, benzylpenicillin, and JBP485. Km and Vmax values of entecavir were 250 μM and 0.83 nmol/mg protein/30s (OAT1) and 23 μM and 1.1 nmol/mg protein/30 s (OAT3), respectively. Entecavir is the substrate of OAT1, OAT3, and OCT. Moreover, OAT1 and OAT3 are the targets of DDI between entecavir and JBP485.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / pharmacokinetics
  • Dipeptides / metabolism
  • Drug Interactions
  • Guanine / administration & dosage
  • Guanine / analogs & derivatives*
  • Guanine / pharmacokinetics
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Kidney / metabolism
  • Male
  • Organic Anion Transport Protein 1 / genetics
  • Organic Anion Transport Protein 1 / metabolism*
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Peptide Transporter 1
  • Peptides, Cyclic / administration & dosage*
  • Peptides, Cyclic / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Symporters / genetics


  • Antiviral Agents
  • Dipeptides
  • JBP 485
  • Organic Anion Transport Protein 1
  • Organic Anion Transporters, Sodium-Independent
  • Peptide Transporter 1
  • Peptides, Cyclic
  • SLC15A1 protein, human
  • Symporters
  • organic anion transport protein 3
  • glycylsarcosine
  • entecavir
  • Guanine