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

Fukumori, Shiro; Masago, Miki; Ishida, Kazuya; Kayano, Yuichiro; Taguchi, Masato; Hashimoto, Yoshiaki

doi:10.1002/bdd.679

Cited by 4 publications

(2 citation statements)

References 21 publications

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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%

“…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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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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Organic anion, organic cation and zwitterion transporters of the SLC22 and SLC47 superfamily (OATs, OCTs, OCTNs and MATEs)

Lai¹

2013

Transporters in Drug Discovery and Development

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Rapid Stimulating Effect of the Antiarrhythmic Agent Amiodarone on Absorption of Organic Anion Compounds

Segawa

Ogura

Seki

et al. 2013

Drug Metabolism and Pharmacokinetics

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In a clinical setting, changes in pharmacokinetics due to drug-drug interactions can often directly affect the therapeutic safety and efficacy of drugs. Recently, interest has been shown in drug-drug interactions in the intestine. It is now recognized that changes in the functions of drug transporters substantially influence the absorption of administered drugs from the intestine. Amiodarone (AMD) is a potent drug used in the treatment of serious supraventricular and ventricular tachyarrhythmias. Despite its potent pharmacological effects, its wide clinical use is precluded by drug-drug interactions. In this study, we characterized the transporter function between AMD and various compounds in human intestinal model Caco-2 cells. AMD significantly and rapidly increased the uptake of [(3)H]estrone-3-sulfate (E-3-S) for 5 min. The apical-to-basal transport of [(3)H]E-3-S was significantly increased by AMD. The AMD-stimulated [(3)H]E-3-S uptake was inhibited by organic anion transporting polypeptide (OATP) substrates. Caco-2 cells treated with AMD showed increased OATP2B1 expression on the cell surface. AMD also increased the absorption of sulfobromophthalein (BSP), which is a typical organic anion compound, and the expression level of Oatp2b1 at the membrane in in vivo experiments. The results indicate that AMD induces OATP2B1/Oatp2b1 expression at the membrane in the intestine and enhances absorption of organic anion compounds.

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

Cited by 4 publications

References 21 publications

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

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

Organic anion, organic cation and zwitterion transporters of the SLC22 and SLC47 superfamily (OATs, OCTs, OCTNs and MATEs)

Rapid Stimulating Effect of the Antiarrhythmic Agent Amiodarone on Absorption of Organic Anion Compounds

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