The role of nucleoside transporters in the erythrocyte disposition and oral absorption of ribavirin in the wild-type and equilibrative nucleoside transporter 1(-/-) mice

Christopher J. Endres, Aaron M. Moss, Rajgopal Govindarajan, Doo Sup Choi, Jashvant D. Unadkat

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Abstract

Ribavirin [1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide] is the treatment of choice for hepatitis C virus infection. Ribavirin is a substrate of several nucleoside transporters, including the equilibrative nucleoside transporter (Ent) and the concentrative nucleoside transporter 2. To determine the role of Ent1 in ribavirin absorption and erythrocyte distribution, we examined its pharmacokinetics in Ent1-null mice. After intravenous administration, we found that the erythrocyte area under the curve (AUC 0-12 h) was reduced 3.05-fold along with 2.63-fold reduction of erythrocyte versus plasma AUC ratio in the Ent1(-/-) mice, whereas there was no significant difference in the plasma AUC0-12 h between Ent1(+/+) and Ent1(-/-) mice. After 48 h, we found a similar fraction of ribavirin or total radioactivity excreted in the urine between the Ent1(+/+) and Ent1(-/-) mice. After oral administration of three different doses, 0.024, 0.24, and 6.1 mg/kg, we found that the dose-normalized plasma AUC0-12 h of ribavirin was 69.7 ± 12.0, 20.7 ± 1.5, and 18.3 ± 2.7 min/l, respectively, in the Ent1(+/+) mice and 18.9 ± 2.8, 13.0 ± 0.5, and 12.2 ± 1.0 min/l, respectively, in the Ent1(-/-) mice. It is interesting that at the highest dose, the dose-normalized plasma AUC 0-30 min, AUC0-12 h, and Cmax in the Ent1(+/+) mice were decreased 4.0-, 3.8-, and 3.4-fold, respectively, compared with the lowest dose, suggesting absorption was saturated at the highest dose we used. The dose-normalized plasma AUC0-12 h was 3.7- and 1.5-fold lower at the lowest and the highest dose, respectively, in the Ent1(-/-) mice compared with those of the Ent1(+/+) mice. Our findings indicate that Ent1 plays a significant role in the oral absorption and erythrocyte distribution of ribavirin.

Original languageEnglish (US)
Pages (from-to)287-296
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume331
Issue number1
DOIs
StatePublished - Oct 2009

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Nucleoside Transport Proteins
Ribavirin
Erythrocytes
Area Under Curve
mouse SLC29A1 protein
Virus Diseases
Hepacivirus
Intravenous Administration
Radioactivity
Oral Administration
Pharmacokinetics
Urine

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

The role of nucleoside transporters in the erythrocyte disposition and oral absorption of ribavirin in the wild-type and equilibrative nucleoside transporter 1(-/-) mice. / Endres, Christopher J.; Moss, Aaron M.; Govindarajan, Rajgopal; Choi, Doo Sup; Unadkat, Jashvant D.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 331, No. 1, 10.2009, p. 287-296.

Research output: Contribution to journalArticle

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abstract = "Ribavirin [1-(β-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide] is the treatment of choice for hepatitis C virus infection. Ribavirin is a substrate of several nucleoside transporters, including the equilibrative nucleoside transporter (Ent) and the concentrative nucleoside transporter 2. To determine the role of Ent1 in ribavirin absorption and erythrocyte distribution, we examined its pharmacokinetics in Ent1-null mice. After intravenous administration, we found that the erythrocyte area under the curve (AUC 0-12 h) was reduced 3.05-fold along with 2.63-fold reduction of erythrocyte versus plasma AUC ratio in the Ent1(-/-) mice, whereas there was no significant difference in the plasma AUC0-12 h between Ent1(+/+) and Ent1(-/-) mice. After 48 h, we found a similar fraction of ribavirin or total radioactivity excreted in the urine between the Ent1(+/+) and Ent1(-/-) mice. After oral administration of three different doses, 0.024, 0.24, and 6.1 mg/kg, we found that the dose-normalized plasma AUC0-12 h of ribavirin was 69.7 ± 12.0, 20.7 ± 1.5, and 18.3 ± 2.7 min/l, respectively, in the Ent1(+/+) mice and 18.9 ± 2.8, 13.0 ± 0.5, and 12.2 ± 1.0 min/l, respectively, in the Ent1(-/-) mice. It is interesting that at the highest dose, the dose-normalized plasma AUC 0-30 min, AUC0-12 h, and Cmax in the Ent1(+/+) mice were decreased 4.0-, 3.8-, and 3.4-fold, respectively, compared with the lowest dose, suggesting absorption was saturated at the highest dose we used. The dose-normalized plasma AUC0-12 h was 3.7- and 1.5-fold lower at the lowest and the highest dose, respectively, in the Ent1(-/-) mice compared with those of the Ent1(+/+) mice. Our findings indicate that Ent1 plays a significant role in the oral absorption and erythrocyte distribution of ribavirin.",
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