Contribution of Na+-independent nucleoside transport to ribavirin uptake in the rat intestine and human epithelial LS180 cells
ABSTRACT The aim of the present study was to characterize the intestinal absorption of ribavirin (1-beta-d-ribofuranosyl-1, 2, 4-trizole-3-carboxamide). We evaluated the contribution of Na(+)-dependent and -independent transport to ribavirin absorption in the rat intestine using an in situ closed loop method. In addition, we performed pharmacokinetic analysis of the uptake of ribavirin in human intestinal epithelial LS180 cells, and also evaluated the effect of extracellular Na(+) concentration and an inhibitor of the Na(+)-independent equilibrative nucleoside transporter, nitrobenzylmercaptopurine ribonucleoside (NBMPR), on the uptake of ribavirin in the cells. In the presence and also absence of Na(+) in rat intestinal loops, more than 80% of the administered dose (50 microg at a concentration of 100 microg/ml=409 microM) of ribavirin was absorbed in 40 min. The absorption of ribavirin in the rat intestine was significantly reduced by coadministration of 10 mg/ml (=37.3 mM) inosine. In LS180 cells, 100 microM ribavirin was taken up time-dependently, and the influx clearance of the drug was similar to the efflux clearance. Five mM inosine and mizoribine reduced the uptake of 100 microM ribavirin in LS180 cells. The absence of extracellular Na(+) decreased the uptake of 100 microM ribavirin only weakly in the cells, whereas the uptake of 100 microM-2 mM ribavirin was markedly decreased by 100 microM NBMPR. These findings suggested that Na(+)-independent nucleoside transport contributes significantly to intestinal absorption of ribavirin at relatively high concentrations (>or=100 microM).
- SourceAvailable from: Nobuhiro Mori
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- "This indicated that the intestinal absorption of mizoribine is mediated by CNT1 and CNT2. The suppression of ribavirin uptake by LS180 cells in the presence of mizoribine (5 mM) is also reported by Takaai et al. . In the study by Mori et al. , bile and bile salts such as sodium cholate and sodium glycocholate (10 mM) were also found to cause interaction with mizoribine. "
ABSTRACT: Mizoribine is administered orally and excreted into urine without being metabolized. Many research groups have reported a linear relationship between the dose and peak serum concentration, between the dose and AUC, and between AUC and cumulative urinary excretion of mizoribine. In contrast, a significant interindividual variability, with a small intraindividual variability, in oral bioavailability of mizoribine is also reported. The interindividual variability is mostly considered to be due to the polymophisms of transporter genes. Methotrexate (MTX) is administered orally and/or by parenteral routes, depending on the dose. Metabolic enzymes and multiple transporters are involved in the pharmacokinetics of MTX. The oral bioavailability of MTX exhibits a marked interindividual variability and saturation with increase in the dose of MTX, with a small intraindividual variability, where the contribution of gene polymophisms of transporters and enzymes is suggested. Therapeutic drug monitoring of both mizoribine and MTX is expected to improve their clinical efficacy in the treatment of rheumatoid arthritis.Pharmaceuticals 12/2012; 5(8):802-836. DOI:10.3390/ph5080802
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ABSTRACT: It was reported previously that specific levofloxacin uptake in Caco-2 cells was inhibited by nicotine, enalapril, L-carnitine and fexofenadine. The aim of the present study was to characterize the cellular uptake of levofloxacin using another human intestinal cell line, LS180. Levofloxacin uptake in LS180 cells was temperature-dependent and optimal at neutral pH, but was Na(+)-independent. The rank order of inhibitory effects of the four compounds on [(14)C] levofloxacin uptake in LS180 cells was nicotine>enalapril>L-carnitine>fexofenadine, which is consistent with that in Caco-2 cells. The mRNA levels of OATP1A2, 1B1, 1B3 and 2B1 in LS180 cells were markedly different from those in Caco-2 cells, and OATP substrates/inhibitors had no systematic effect on the levofloxacin uptake. The mRNA levels of OCTN1 and 2 in LS180 cells were similar to those in Caco-2 cells. However, the inhibitory effect of nicotine on L-[(3)H]carnitine uptake was much less potent than that of unlabeled L-carnitine. These results indicate that the specific uptake system for levofloxacin in LS180 cells is identical/similar to that in Caco-2 cells, but that OATPs and OCTNs contribute little to levofloxacin uptake in the human intestinal epithelial cells.Biopharmaceutics & Drug Disposition 11/2009; 30(8):448-56. DOI:10.1002/bdd.679 · 2.34 Impact Factor
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ABSTRACT: The absorption sites of mizoribine (an imidazole nucleoside) and ribavirin (a purine nucleoside) in the small intestine were evaluated in rats. The intestinal absorption of mizoribine is known to be mediated by rat concentrative nucleoside transporter (CNT)1 and CNT2. In contrast, the absorption mechanism of ribavirin in rats is not yet fully understood. Thus, the intestinal absorption of ribavirin was characterized firstly. In in-situ jejunum loop studies, the absorption percentage of ribavirin at a dose of 25mg/kg was significantly lower than those after 1mg/kg and 5mg/kg doses. Coadministration of adenosine, inosine and mizoribine, but not thymidine and gemcitabine, significantly suppressed the intestinal absorption of ribavirin, indicating that ribavirin absorption is mediated by CNT2 in rats. In in-situ loop studies, mizoribine and ribavirin were absorbed to the same extents both in the proximal and distal small intestine. In vivo study was carried out using mizoribine, in which the gastric emptying rates altered by a subcutaneous injection of metoclopramide or scopolamine butylbromide exerted no significant effects on the values of peak plasma level (Cmax), area under the plasma concentration-time profile from 0 to 6h (AUC(0-6)), and urinary excretion percentage of mizoribine given orally, though the time to reach Cmax (Tmax) of mizoribine was altered by each treatment. In conclusion, mizoribine and ribavirin were found to be absorbed efficiently to the same extents from the whole small intestine. Also, the altered gastric emptying rates exerted no significant effects on the oral bioavailabilities of mizoribine and ribavirin.European journal of pharmacology 12/2009; 628(1-3):214-9. DOI:10.1016/j.ejphar.2009.11.048 · 2.53 Impact Factor