The Apical Uptake Transporter of Levofloxacin is Distinct from the Peptide Transporter in Human Intestinal Epithelial Caco-2 Cells

Fukumori, Shiro; Murata, Tsuyoshi; Takaai, Mari; Tahara, Katsutoshi; Taguchi, Masato; Hashimoto, Yoshiaki

doi:10.2133/dmpk.23.373

Cited by 7 publications

(12 citation statements)

References 9 publications

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“…Indeed, it was discovered that several quinolone antibiotics inhibited the uptake of Phe‐Ψ‐Ala. In a previous study, LVFX inhibited [ 3 H]Gly‐Sar uptake into Caco‐2 cells, but LVFX uptake into Caco‐2 cells was not inhibited by PEPT1 inhibitors . Our results were supported by the study.…”

Section: Discussionsupporting

confidence: 89%

Possible interaction of quinolone antibiotics with peptide transporter 1 in oral absorption of peptide‐mimetic drugs

Arakawa

Kamioka

Kanagawa

et al. 2016

Biopharm & Drug Disp

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The study investigated whether quinolone antibiotics inhibit the PEPT1-mediated uptake of its substrates. Among the quinolones examined, lomefloxacin, moxifloxacin (MFLX) and purlifloxacin significantly inhibited the uptake of PEPT1 substrate phenylalanine-Ψ(CN-S)-alanine (Phe-Ψ-Ala) in HeLa/PEPT1 cells to 31.6 ± 1.3%, 27.6 ± 2.9%, 36.8 ± 2.2% and 32.6 ± 1.4%, respectively. Further examination showed that MFLX was an uncompetitive inhibitor, with an IC50 value of 4.29 ± 1.29 mm. In addition, MFLX significantly decreased the cephalexin and valacyclovir uptake in HeLa/PEPT1 cells. In an in vivo study in rats, the maximum plasma concentration (C(max)) of orally administered Phe-Ψ-Ala was significantly decreased in the presence of MFLX (171 ± 1 ng/ml) compared with that in its absence (244 ± 9 ng/ml). The area under the concentration-time curve (AUC) of orally administered Phe-Ψ-Ala in the presence of MFLX (338 ± 50 ng/ml · h) tended to decrease compared with that in its absence (399 ± 75 ng/ml · h). The oral bioavailability of Phe-Ψ-Ala in the presence and absence of MFLX was 41.7 ± 6.2% and 49.2 ± 9.2%, respectively. The results indicate that administration of quinolone antibiotics concomitantly with PEPT1 substrate drugs may potentially result in drug-drug interaction.

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Section: Discussionsupporting

confidence: 89%

Possible interaction of quinolone antibiotics with peptide transporter 1 in oral absorption of peptide‐mimetic drugs

Arakawa

Kamioka

Kanagawa

et al. 2016

Biopharm & Drug Disp

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“…This cell line possesses characteristics of the small intestine (e.g., expression of microvillus), and has also been used as an in vitro model of the intestine. [8][9][10][11]20) The cellular uptake of quinidine in LS180 cells was temperature-and pH-dependent, and was inhibited by hydrophobic cationic drugs with the following rank order of inhibitory effect: imipramineϾquinidineϾ diphenhydramineϷpyrilamineϾprocainamide (Figs. 2-5).…”

Section: Discussionmentioning

confidence: 99%

“…After the equilibration period, the radio-labeled drug (0.33 mCi/ml) was applied to the apical chamber (0.75 ml) to examine apical-to-basolateral transcellular transport. 1,7,8) A volume (50 ml) of medium in the basolateral chamber (1.5 ml) was then collected 30, 60, and 90 min after the radio-labeled drug was applied. Cells on the porous membrane were collected following the last collection of medium.…”

Section: Methodsmentioning

confidence: 99%

“…1,7,8) When transcellular drug transport is examined under the condition where the unlabeled drug concentration in the monolayer is equilibrated with that of the incubation medium in the apical and basolateral chambers, transport data for a small amount of radiolabeled drug can be analyzed using the linear pharmacokinetic model. That is, the following mass balance equations were prepared for pharmacokinetic analysis: (1) (2) (3) where X A , X B , and X C are the amounts of radio-labeled drugs in the apical chamber, basolateral chamber, and monolayer determined at time t, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Radio-labeled mannitol was used to estimate the extracellular trapping of cationic drugs. [8][9][10][11] The cellular uptake of [ 3 H]quinidine and [ 14 C]procainamide was analyzed in a model-dependent manner using NONMEM software, as described previously. 9,10) The following mass balance equations were prepared for the pharmacokinetic analysis: (6) (7) where X M and X C are the amount of radio-labeled drugs in the incubation medium and the cells determined at time t, respectively.…”

Section: Methodsmentioning

confidence: 99%

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Membrane Transport Mechanisms of Quinidine and Procainamide in Renal LLC-PK1 and Intestinal LS180 Cells

Masago

Takaai

Sakata

et al. 2010

Biological & Pharmaceutical Bulletin

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We previously evaluated the renal excretion mechanism of quinidine, which is a tertiary amine compound, using porcine kidney epithelial LLC-PK 1 cells and P-glycoprotein (P-gp)-expressed LLC-GA5-COL150 cells.1) The transepithelial transport of quinidine in the basolateral-to-apical direction in LLC-PK 1 cells was similar to that in the opposite direction. In contrast, quinidine was transported actively in the basolateral-to-apical direction in LLC-GA5-COL150 cells. The results suggested that P-gp is mainly responsible for the tubular secretion of quinidine in the kidney. 1) We also evaluated the intestinal absorption mechanism of quinidine using human intestinal epithelial Caco-2 cells.2) The temperaturedependent uptake of quinidine in Caco-2 cells grown on a plastic dish was increased by alkalization of the apical medium, and was inhibited by diphenhydramine and imipramine. The results suggested that a cation transport system was involved in the influx of quinidine at the apical membrane in intestinal epithelial cells. 2)Procainamide, another tertiary amine compound with a pK a value of 9.23, is classified as a type IA antiarrhythmic drug that works by decreasing conduction velocity, and prolonging tissue refractoriness.3) More than 80% of orally administered procainamide is absorbed from the intestine in humans.4) The Kp (octanol/buffer at pH 7.4) value of procainamide is about 0.1, and approximately half of the dose is excreted in the urine as unchanged drug.3-6) However, the mechanisms responsible for the membrane transport of procainamide in intestinal and renal epithelial cells are still unclear.In the present study, the transport characteristics of procainamide in LLC-PK 1 cells were compared with those of quinidine. In addition, we evaluated whether the transport system for quinidine is present in another intestinal cell line, LS180, as well as Caco-2. We also investigated whether the transport system of procainamide in LS180 cells is the same as that of quinidine. Cell Culture and Preparation of Monolayers LLC-PK 1 cells at passage 197 and LS180 cells at passage 38 were obtained from the American Type Culture Collection (Manassas, VA, U.S.A.). These cells were maintained by serial passage in plastic dishes with Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum (Biowest Inc., Nuaille, France) in an atmosphere of 5% CO 2 -95% air at 37°C. MATERIALS AND METHODS MaterialsLLC-PK 1 cells were seeded at a density of 5ϫ10 5 cells/ cm 2 on a 1.12 cm 2 porous membrane (3 mm pore size) in a polyester membrane Transwell ® -Clear insert (Costar, Cambridge, MA, U.S.A.) to evaluate the transcellular transport of cationic drugs. The seeded cells were maintained for 6 d to prepare differentiated cell monolayers. The maturity of the monolayer was judged by transepithelial electrical resistance (TEER). TEER was measured using a Millicell-ERS resistance system (Millipore, Bedford, MA, U.S.A.). LLC-PK 1 cell monolayers whose TEER was above 60 W · cm 2 were used to The aim of the present study was t...

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Temperature‐dependent specific transport of levofloxacin in human intestinal epithelial LS180 cells

Fukumori

Masago

Ishida

et al. 2009

Biopharm & Drug Disp

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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.

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The Apical Uptake Transporter of Levofloxacin is Distinct from the Peptide Transporter in Human Intestinal Epithelial Caco-2 Cells

Cited by 7 publications

References 9 publications

Possible interaction of quinolone antibiotics with peptide transporter 1 in oral absorption of peptide‐mimetic drugs

Possible interaction of quinolone antibiotics with peptide transporter 1 in oral absorption of peptide‐mimetic drugs

Membrane Transport Mechanisms of Quinidine and Procainamide in Renal LLC-PK1 and Intestinal LS180 Cells

Temperature‐dependent specific transport of levofloxacin in human intestinal epithelial LS180 cells

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