title: The role of the equilibrative nucleoside transporter 1 on tissue and fetal distribution of ribavirin in the mouse.
abstract: Ribavirin is used for the treatment of hepatitis C virus (HCV) infection. The equilibrative nucleoside transporter 1 (ENT1) expressed in hepatocytes transports ribavirin into the liver, the site of efficacy of the drug. However, it is still unclear whether ENT1 plays a dominant role in the hepatic distribution of the drug in vivo. In addition, due to fetal toxicity, administration of ribavirin to pregnant women with HCV infection is contraindicated. ENT1 might play a role in the fetal distribution and therefore the fetal toxicity of ribavirin. The aim of the present study was to investigate the in vivo contribution of ENT1 to the tissue distribution of ribavirin. When compared with that in Ent1(+/+) mice, the ribavirin tissue to plasma concentration ratio (including phosphorylated metabolites) in Ent1(-/-) mice at 15 min and 6 h after intravenous [(3) H]-ribavirin (3 mg/kg) administration was consistently and significantly decreased in the liver and the pancreas. Likewise, when compared with the Ent1(+/+) mice, the fetal distribution of ribavirin at 15 min after administration was significantly reduced in Ent1(-/-) fetuses and placenta. In contrast, there was no significant difference between Ent1(+/+), Ent1(+/-) and Ent1(-/-) mice in the fetal or placental to maternal plasma ribavirin concentration ratio at 2 h after ribavirin administration. The findings in the present study suggest that ENT1 plays a pivotal role in the distribution of ribavirin into tissues including the liver and pancreas, but affects only the rate, but not the extent, of ribavirin distribution into the fetus. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Pharmaceutics, Seattle, Washington, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Endres
authors.affiliation: Department of Pharmaceutics, Seattle, Washington, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Moss
authors.affiliation: Department of Pharmaceutics, Seattle, Washington, USA.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishida
authors.affiliation: Department of Pharmaceutics, Seattle, Washington, USA.
authors.forename: Rajgopal
authors.initials: R
authors.lastname: Govindarajan
authors.affiliation: Department of Pharmaceutics, Seattle, Washington, USA. jash@u.washington.edu.
authors.forename: Jashvant D
authors.initials: JD
authors.lastname: Unadkat
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000378:metabolism*; D018345:Mice, Knockout; D011247:Pregnancy; D012254:Ribavirin / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000998:Antiviral Agents; D033721:Equilibrative Nucleoside Transporter 1; C498476:SLC29A1 protein, mouse; D012254:Ribavirin
keywords: Ribavirin; equilibrative nucleoside transporter; fetal distribution; hepatitis C; tissue distribution