P-glycoprotein-mediated transport of digitoxin, α-methyldigoxin and β-acetyldigoxin

Pauli‐Magnus, Christiane; Mürdter, Thomas E.; A, Godel; Mettang, Thomas; Eichelbaum, Michel; Klotz, Ulrich; Fromm, Martin F.

doi:10.1007/s002100000354

Cited by 47 publications

(30 citation statements)

References 23 publications

(39 reference statements)

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“…In humans, digoxin uptake is not mediated by OATP1B1, OATP1B3, and OATP2B1 and very little hepatic metabolism occurs. Both species excrete digoxin into bile via MDR1/Mdr1, however (Annaert et al, 2001;Pauli-Magnus et al, 2001;Taipalensuu et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes

Kimoto¹,

Chupka²,

Xiao³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Digoxin is a drug that is commonly used to treat congestive heart failure. Because of digoxin's narrow therapeutic index, patients are susceptible to drug-drug interaction-mediated cardiotoxicity. Digoxin is primarily cleared renally; however, a significant component of clearance is due to multidrug resistance 1-mediated transport into bile. Digoxin is reported to be actively transported into human hepatocytes by the organic anion-transporting polypeptide 1B3 (OATP1B3); however, further characterization has not been fully described.

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Section: Discussionmentioning

confidence: 99%

Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes

Kimoto¹,

Chupka²,

Xiao³

et al. 2010

Drug Metab Dispos

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“…To achieve this, Caco-2 cells were cultured as described above at 37 °C. After 36 hours, to allow proper attachment, cells were exposed to either 100 µM amantadine (hOCT1&2), 100 µM cimetidine (hOCT1&2&3) [37], 100 µM desipramine (hOCT1&2&3), 10 µM β-estradiol (hOCT1&3) or 10 µM verapamil (hOCT1&P-gp) [28,35,36] for 15 min. Then attached cells were exposed to 10 µM erlotinib, gefitinib, sorafenib, sunitinib, crizotinib or 1 µM dasatinib for 2 hours at 37 °C.…”

Section: Effect Of Specific Oct Inhibitorsmentioning

confidence: 99%

“…Trans epithelial electral resistance (TEER) was measured using a Millicell-ERSvoltmeter to verify the quality of the Caco-2 cell monolayers. Monolayers with TEER values determined below 165 Ω cm 2 were discarded [35]. Next, the HBSS and hOCT inhibitor solution were replaced for 300 l of 20 M erlotinib, gefitinib, sorafenib, sunitinib, dasatinib or crizotinib alone or in combination with 100 M cimetidine, desipramine or 10 M verapamil (apical side) and 1 ml HBSS + 5 % BSA (basolateral side).…”

Section: Differentiated Caco-2 Cells As a Model For Gut Epithelial Trmentioning

confidence: 99%

“…The hOCT family can be inhibited by amantadine (hOCT1&2), cimetidine (hOCT1&2&3) [40], desipramine (hOCT1&2&3), β-estradiol (hOCT1&3) and verapamil (hOCT1&P-gp) [27,35,36]. All five hOCT inhibitors decreased gefitinib accumulation, demonstrating that hOCT is involved in the uptake of gefitinib.…”

Section: Transporter Dependent Hoct Dependent Accumulation In Caco-2 mentioning

confidence: 99%

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Transport of six tyrosine kinase inhibitors: active or passive?

Honeywell¹,

Hitzerd²,

Kathmann³

et al. 2016

ADMET DMPK

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“…A number of MDR modulators have pronounced bioac-tivities of their own such as verapamil and cyclosporine A, 10 which limit their clinical usefulness while most inhibitors of MDR are transporter substrates thus requiring high concentrations to overcome MDR. 11,12 To the best knowledge of the authors, these severe limitations have resulted in there being no clinically available MDR reversal agents to date and hence such medication is urgently required.…”

mentioning

confidence: 99%

1-[4-(2-Aminoethoxy)phenylcarbonyl]-3,5-bis-(benzylidene)-4-oxopiperidines: A novel series of highly potent revertants of P-glycoprotein associated multidrug resistance

Das¹,

Molnár²,

Baráth³

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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The 1-[4-(2-aminoethoxy)phenylcarbonyl]-3,5-bis-(benzylidene)-4-oxopiperidines 5-8 are a novel cluster of highly potent P-glycoprotein dependent multidrug resistance (MDR) revertants. Using a concentration of 4 μg/mL, these compounds possess 11-43 times the potency of verapamil in reversing MDR in murine L-5178 lymphoma cells transfected with the human MDR1 gene. Structure-activity relationships reveal that the attachment of the N-aroyl group to various 3,5-bis(benzylidene)-4-piperidones is essential for MDR reversal to occur. In terms of potencies, the 1-piperidinyl group is the preferred terminal amine while the 4-methyl and 4-chloro substituents are the optimal groups for placement in the benzylidene aryl rings. KeywordsMultidrug resistance; Structure1-activity relationships; Physicochemical constants; N-Aroyl-3,5- bis(benzylidene)-4-piperidonesThe principal objective of our laboratory is finding chemical approaches to counteract the ravages caused by cancer. A recent emphasis has been directed to finding compounds which reverse the vexatious problem of multidrug resistance (MDR). 1,2 The study described herein reveals the remarkable potencies of a novel series of P-glycoprotein (P-gp) associated MDR revertants namely the 1-[4-(2-aminoethoxy)phenylcarbonyl]-3,5-benzylidene-4-oxopiperidines.The problem of drug resistance occurs in many tumours and leads to an increased drug efflux from the neoplasms causing decreased intracellular drug concentrations thereby reducing the effectiveness of anticancer drugs. The mechanism of drug resistance is multifactorial but principally it is due to the overexpres-sion of P-gp, which is a member of A number of studies revealed the increased potencies of anti-cancer drugs when administered with MDR revertants. 6,7 These chemosensitizers act in different ways, namely by binding to P-gp, inhibiting the efflux of the anticancer drugs from the tumours and reducing the binding of cytotoxins to P-gp. 8,9 In addition these compounds may reduce P-gp synthesis and/or inhibit MDR gene expression. A number of MDR modulators have pronounced bioac-tivities of their own such as verapamil and cyclosporine A, 10 which limit their clinical usefulness while most inhibitors of MDR are transporter substrates thus requiring high concentrations to overcome MDR. 11,12 To the best knowledge of the authors, these severe limitations have resulted in there being no clinically available MDR reversal agents to date and hence such medication is urgently required.The design of a novel cluster of MDR revertants was made as follows. First, the common molecular features of a number of MDR modulators are their hydrophobicity, having two aryl rings and atoms capable of hydrogen bonding as well as bearing a positive charge at neutral pH. 13,14 Second, in terms of specific groups to be incorporated into the candidate MDR revertants, previous investigations from this laboratory revealed that various compounds which contain the 1,5-diaryl-3-oxo-1,4-pentadienyl moiety reverse MDR. 1,2 In addition, the 4-(2-a...

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P-glycoprotein-mediated transport of digitoxin, α-methyldigoxin and β-acetyldigoxin

Cited by 47 publications

References 23 publications

Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes

Characterization of Digoxin Uptake in Sandwich-Cultured Human Hepatocytes

Transport of six tyrosine kinase inhibitors: active or passive?

1-[4-(2-Aminoethoxy)phenylcarbonyl]-3,5-bis-(benzylidene)-4-oxopiperidines: A novel series of highly potent revertants of P-glycoprotein associated multidrug resistance

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