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).
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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: The purpose of the present study was to investigate the roles of transporters in the renal excretion of entecavir. We analyzed the effect of probenecid, cimetidine, sulfobromophthalein sodium (BSP), verapamil, inhibitors of organic anion transporter (OAT), organic cation transporter (OCT), multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein respectively, on the excretion of entecavir. The area under plasma concentration-time curve (AUC), body clearance, and renal clearance of entecavir was examined in each group. After intravenous coadministration with entecavir in conscious rats, cimetidine, probenecid, BSP and verapamil significantly increased the AUC of entecavir by 40.07%, 48.78%, 37.49%, and 54.58%, and reduced the body clearance by 27.14%, 31.69%, 29.79%, and 42.17%, respectively. Then the effects of these inhibitors on the renal clearance of entecavir in unconscious rats were studied. Coadministration of cimetidine and probenecid increased the steady plasma concentration of entecavir by 127.61% and 169.46%, reduced the renal clearance by 50.47% and 67.76%, and decreased the excretion ratio by 44.81% and 64.16% compared to initial values. However, the effects of BSP and verapamil were slight. Cimetidine and probenecid also increased the concentration of entecavir in kidney from 34.00±0.80ng/mL to 55.19±4.92ng/mL and 49.92±1.53ng/mL, while the concentration of entecavir in kidney from BSP and verapamil groups was 30.96±0.81ng/mL and 35.72±7.30ng/mL, respectively. These results suggest that cimetidine and probenecid inhibit the renal excretion of entecavir in rats, which indicates the most likely involvement of organic anion and cation transporters in the renal excretion of entecavir.Life sciences 04/2011; 89(1-2):1-6. DOI:10.1016/j.lfs.2011.03.018 · 2.30 Impact Factor
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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 · 2.18 Impact Factor