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 (AUC0–12 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 AUC0–30 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.
- ENT/Ent, equilibrative nucleoside transporter
- CNT, concentrative nucleoside transporter
- RMP, ribavirin 5′-monophosphate
- RTP, ribavirin triphosphate
- AUC, area under the curve
- dH2O, deionized water
- RDP, ribavirin 5′-diphosphate
- HPLC, high-performance liquid chromatography
- RTCOOH, 1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxylic acid
- TCONH2, 1,2,4-triazole-3-carboxamide
- TCOOH, 1,2,4-triazole-3-carboxylic acid
- D, dose normalized.
Footnotes
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This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM54447] (to J.D.U.); and the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant AA015164] (to D.-S.C.); and the Eli Lilly Foundation (to C.J.E.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
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↵1 Current affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc., Seattle, Washington.
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↵2 Current affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia.
- Received March 23, 2009.
- Accepted July 13, 2009.
- © 2009 by the American Society for Pharmacology and Experimental Therapeutics
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