Pharmacokinetic Characterization of Transcellular Transport and Drug Interaction of Digoxin in Caco-2 Cell Monolayers

Aiba, Tetsuya; Ishida, Kazuya; Yoshinaga, Mariko; Okuno, Marie; Hashimoto, Yoshiaki

doi:10.1248/bpb.28.114

Cited by 14 publications

(26 citation statements)

References 23 publications

(31 reference statements)

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“…9,10) Moreover, in spite of the expression of UGTs and CYP3A4 in the intestine, it is also unclear whether the intestine is involved in the presystemic metabolism of carvedilol. 12,21) In the present study, we investigated the metabolism of R-and S-carvedilol in human intestinal epithelial Caco-2 cells. Treatment of Caco-2 cells with b-NF and VD 3 induces UGTs and CYP3A4, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…12,13) In addition, several UGTs, such as UGT1A1, 1A6, and 2B7, are expressed in Caco-2 cells, and the expression of some UGTs is induced by aromatic hydrocarbon receptor (AhR) ligands, such as b-naphthoflavone (b-NF).…”

mentioning

confidence: 99%

“…It also expresses various transporters and efflux pumps such as P-glycoprotein. 11,12) Therefore, it has been utilized to examine the mechanism responsible for the intestinal absorption of various compounds. 12,13) In addition, several UGTs, such as UGT1A1, 1A6, and 2B7, are expressed in Caco-2 cells, and the expression of some UGTs is induced by aromatic hydrocarbon receptor (AhR) ligands, such as b-naphthoflavone (b-NF).…”

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confidence: 99%

“…11,12) Therefore, it has been utilized to examine the mechanism responsible for the intestinal absorption of various compounds. 12,13) In addition, several UGTs, such as UGT1A1, 1A6, and 2B7, are expressed in Caco-2 cells, and the expression of some UGTs is induced by aromatic hydrocarbon receptor (AhR) ligands, such as b-naphthoflavone (b-NF). 14,15) Therefore, glucuronidation of drugs in the intestine has been studied using Caco-2 cells.…”

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Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Ishida

Honda

Shimizu

et al. 2007

Biological & Pharmaceutical Bulletin

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Carvedilol is a b-adrenoceptor antagonist, and has been clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias. [1][2][3][4] Carvedilol is highly lipophilic and is absorbed rapidly from the gastrointestinal tract after oral administration. Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the blood concentration of R-enantiomer with very low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity. 5,6) Both enantiomers are eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose. 7) Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways.8) Oldham and Clarke reported that oxidative activity for carvedilol is observed in cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2. 9) In addition, Ohno et al. reported that UDP-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol. 10) However, it is still unclear which enzyme is responsible for the stereoselective presystemic clearance of carvedilol. Furthermore, although CYP3A4 and several UGTs are expressed in intestinal epithelial cells, it is also unknown whether the intestine as well as the liver is involved in the first-pass metabolism of carvedilol.The approach for investigating intestinal drug absorption and metabolism is to use human intestinal cell lines, such as the frequently used line Caco-2. This line spontaneously differentiates, after which it shows enterocyte-like morphology and forms polarized monolayers via tight junctions. It also expresses various transporters and efflux pumps such as P-glycoprotein.11,12) Therefore, it has been utilized to examine the mechanism responsible for the intestinal absorption of various compounds. 12,13) In addition, several UGTs, such as UGT1A1, 1A6, and 2B7, are expressed in Caco-2 cells, and the expression of some UGTs is induced by aromatic hydrocarbon receptor (AhR) ligands, such as b-naphthoflavone (b-NF).14,15) Therefore, glucuronidation of drugs in the intestine has been studied using Caco-2 cells. [16][17][18] In contrast, the Caco-2 cell line had not been employed to examine the intestinal metabolism of CYP3A4 substrates due to its lack of CYP3A4 expression. Recently, however, it has been reported that CYP3A4 in Caco-2 cells is induced by 1a,25-dihydroxyvitamin D 3 (VD 3 ). 11,19) The finding suggests that this cell line may also be utilized to investigate intestinal drug metabolism by CYP3A4. In the present study, we investigated whether carvedilol is metabolized stereoselectively in Caco-2 cells, and also evaluated the changes in the metabolic rate of carvedilol in b-NF-and VD 3 -treated Caco-2 cells. MATERIALS AND METHODS MaterialsCarvedilol was kindly supplied by Daiichi Pharmaceutical (Tokyo, Japan). b-NF was obtained from Nacalai Tesque (Kyoto, Japan). VD 3 and 3Ј-azido-3Ј-deoxythimidine (AZT...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Ishida

Honda

Shimizu

et al. 2007

Biological & Pharmaceutical Bulletin

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“…For example, transcellular transport of digoxin was investigated using Caco-2 cells grown on porous membrane filters, and the results indicated that P-gp is involved in the intestinal secretion of digoxin. 6,7) Chiu et al investigated the transcellular transport of another P-gp substrate, cyclosporin A, across Caco-2 cell monolayers to examine the jejunal permeability of the drug. 8) Watanabe et al investigated the effects of progesterone and norethisterone on the apical-to-basolateral and basolateral-to-apical transport of cephalexin, a typical PEPT1 substrate, using Caco-2 cell monolayers cultured on permeable membranes.…”

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Pharmacokinetic Analysis of Transcellular Transport of Levofloxacin across LLC-PK1 and Caco-2 Cell Monolayers

Takaai

Suzuki

Ishida

et al. 2007

Biological & Pharmaceutical Bulletin

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To characterize the membrane transport responsible for the renal excretion and intestinal absorption of levofloxacin, we performed pharmacokinetic analysis of transcellular transport across LLC-PK 1 and Caco-2 cell monolayers. Transcellular transport of levofloxacin in LLC-PK 1 cells was greater in the basolateral-to-apical direction than in the opposite direction. Pharmacokinetic analysis indicated that basolateral uptake was the direction-determining step for the transcellular transport of levofloxacin in LLC-PK 1 cells. The apical efflux clearance of levofloxacin in LLC-PK 1 cells was increased at the medium pH 6 as compared with at pH 8, suggesting that membrane transport characteristics of levofloxacin are apparently similar to those of a prototypical organic cation, tetraethylammonium. On the other hand, transcellular transport of levofloxacin in Caco-2 cells was only slightly greater in the basolateral-to-apical direction than in the opposite direction. The apical efflux clearance of levofloxacin in Caco-2 cells was greater than basolateral efflux clearance, and apical influx clearance was greater than any other membrane transport clearance. In addition, the apical uptake of levofloxacin as well as quinidine in Caco-2 cells was inhibited significantly by nicotine and imipramine. The findings indicated that some transporters are responsible not only for the efflux but also for the influx of levofloxacin at the apical membrane of Caco-2 cells.

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Identifying Clinically Relevant Drug–Drug Interactions With Methadone and Buprenorphine: A Translational Approach to Signal Detection

Miano

Wang

Leonard

et al. 2022

Clin Pharma and Therapeutics

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Methadone and buprenorphine have pharmacologic properties that are concerning for a high risk of drugdrug interactions (DDIs). We performed high-throughput screening for clinically relevant DDIs with methadone or buprenorphine by combining pharmacoepidemiologic and pharmacokinetic approaches. We conducted pharmacoepidemiologic screening via a series of self-controlled case series studies (SCCS) in Optum claims data from 2000 to 2019. We included persons 18 years or older who experienced an outcome of interest during target drug treatment. Exposures were all overlapping medications (i.e., the candidate precipitants) during target drug treatment. Outcomes were opioid overdose, non-overdose adverse effects, and cardiac arrest. We used conditional Poisson regression to calculate rate ratios, accounting for multiple comparisons with semi-Bayes shrinkage. We explored the impact of key study design choices in analyses that varied the exposure definitions of the target drugs and the candidate precipitant drugs. Pharmacokinetic screening was conducted by incorporating published data on CYP enzyme metabolism into an equation-based static model. In SCCS analysis, 1,432 events were included from 248,069 new users of methadone or buprenorphine. In the primary analysis, statistically significant DDIs included gabapentinoids with either methadone or buprenorphine; baclofen with methadone; and benzodiazepines with methadone. In sensitivity analysis, additional statistically significant DDIs included methocarbamol, quetiapine, or simvastatin with methadone. Pharmacokinetic screening identified two moderate-to-strong potential DDIs (clonidine and fluconazole with buprenorphine). The combination of clonidine and buprenorphine was also associated with a significantly increased risk of opioid overdose in pharmacoepidemiologic screening. These DDI signals may be the most important targets for future confirmation studies.

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Pharmacokinetic Characterization of Transcellular Transport and Drug Interaction of Digoxin in Caco-2 Cell Monolayers

Cited by 14 publications

References 23 publications

Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

Pharmacokinetic Analysis of Transcellular Transport of Levofloxacin across LLC-PK1 and Caco-2 Cell Monolayers

Identifying Clinically Relevant Drug–Drug Interactions With Methadone and Buprenorphine: A Translational Approach to Signal Detection

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