Role of the equilibrative and concentrative nucleoside transporters in the intestinal absorption of the nucleoside drug, ribavirin, in wild-type and Ent1(-/-) mice.
Ribavirin is frontline treatment for hepatitis C virus infection. To determine the role of nucleoside transporters in the intestinal absorption of orally administered ribavirin, we perfused the intestines of Ent1(-/-) and wild-type mice, in situ, with [(3)H] ribavirin (20, 200, and 5000 μM) in the presence and absence of sodium. The decrease in luminal ribavirin concentration over 30 min was measured at 5 min intervals. Blood samples were collected approximately every 10 min. Ribavirin plus phosphorylated metabolite concentrations (hereafter referred to as ribavirin) were determined in tissue, blood, and plasma by HPLC fractionation and scintillation counting. There was no significant difference between wild-type and Ent1(-/-) mice in intestinal loss of ribavirin at any ribavirin concentration studied. Perfusions without sodium drastically reduced the intestinal loss of ribavirin in both wild-type and Ent1(-/-) mice. After 20 μM ribavirin perfusions, Ent1(-/-) intestinal tissue contained 8-fold greater ribavirin than wild-type mice (p < 0.01). Ribavirin concentrations in the wild-type intestinal tissue were 70-fold higher after 200 vs 20 μM perfusions (p < 0.001), indicating saturation of intestinal ribavirin efflux and possibly other processes as well. Ribavirin plasma concentrations were significantly higher in wild-type mice (2.7-fold) vs Ent1(-/-) mice at 30 min after the 20 μM perfusion (p < 0.01). These results suggest that, at lower intestinal concentrations of ribavirin, concentrative and equilibrative nucleoside transporters are important in the intestinal absorption of ribavirin. At higher intestinal concentrations, these transporters are saturated and other processes in the intestine (transport and/or metabolism) play an important role in the absorption of ribavirin.
Department of Pharmaceutics, University of Washington, Seattle, Washington 98195-7610, United States.
Aaron M
AM
Moss
Christopher J
CJ
Endres
Ana
A
Ruiz-Garcia
Doo-Sup
DS
Choi
Jashvant D
JD
Unadkat
D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D004285:Dogs; D033721:Equilibrative Nucleoside Transporter 1 / Q000378:metabolism*; D005260:Female; D007408:Intestinal Absorption; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D033703:Nucleoside Transport Proteins / Q000378:metabolism*; D009705:Nucleosides / Q000493:pharmacokinetics*; D012254:Ribavirin / Q000097:blood / Q000493:pharmacokinetics*; D012964:Sodium / Q000378:metabolism
D033721:Equilibrative Nucleoside Transporter 1; D026901:Membrane Transport Proteins; D033703:Nucleoside Transport Proteins; D009705:Nucleosides; C498476:SLC29A1 protein, mouse; D012254:Ribavirin; D012964:Sodium