Involvement of P-glycoprotein and multidrug resistance associated protein 1 on the transepithelial transport of a mercaptoacetamide-based histone-deacetylase inhibitor in Caco-2 cells.

Biological & Pharmaceutical Bulletin
Zacharoula Konsoula, Mira Jung

Abstract

Oral bioavailability is one of the important criteria for development of a drug-lead candidate. In this study, the absorptive characteristics and the efflux mechanism of a mercaptoacetamide-based histone deacetyalse (HDAC) inhibitor, coded as W2, were investigated using Caco-2 cells. The transport of W2 was asymmetric as indicated by 1.85 fold higher basolateral to apical (BL to AP) than apical to basolateral (AP to BL) flux. Such asymmetry was associated with multidrug resistance associated protein 1 (MRP1) and P-glycoprotein (P-gp), as evidenced by specific inhibition of these proteins. In the presence of verapamil and cyclosporin A, potent inhibitors of P-gp, the apparent permeability ratio (P(app) BL to AP/P(app) AP to BL) of W2 was decreased from 1.85 to 0.73 and 1.03, respectively, and the absorption from apical to basolateral side was enhanced from 13.3+/-0.2x10(-6) cm/s to 17.3+/-0.12x10(-6) cm/s and 19+/-0.3x10(-6) cm/s, respectively. Upon addition of quinidine, a mixed P-gp and MRP1 inhibitor, the permeation of W2 from the apical side was significantly increased (P(app) 17.1+/-0.32x10(-6) cm/s) while the efflux was inhibited (P(app) 21.3+/-0.19x10(-6) cm/s). Furthermore, the influence of the MRP1 inhibitors, indometha...Continue Reading

References

Jul 17, 1998·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·M D DeMario, M J Ratain
Aug 28, 1998·The Journal of Pharmacy and Pharmacology·R SandströmH Lennernäs
Jun 24, 1999·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·C Meaney, C O'Driscoll
Aug 25, 2000·Investigational New Drugs·L van ZuylenJ Verweij
Mar 22, 2001·Advanced Drug Delivery Reviews·P ArturssonK Luthman
Apr 20, 2001·Bioorganic & Medicinal Chemistry·A R MaguireS Touhey
Jul 11, 2001·Pharmacotherapy·C J MathenyG M Pollack
Jan 24, 2002·Journal of Bioenergetics and Biomembranes·G D KruhM G Belinsky
Nov 16, 2002·Journal of Pharmaceutical Sciences·Han-Joo MaengChang-Koo Shim
Sep 2, 2003·Pharmaceutical Research·Michael D PerloffDavid J Greenblatt
Jan 20, 2004·Toxicology and Applied Pharmacology·Jean-Luc BrunetLuc P Belzunces
Jun 24, 2004·The Journal of Pharmacology and Experimental Therapeutics·Hannah M Prime-ChapmanBarry H Hirst
Aug 18, 2004·International Journal for Parasitology·Julio C CarreroJuan P Laclette
Dec 18, 2004·Bioorganic & Medicinal Chemistry Letters·Takayoshi SuzukiNaoki Miyata
Feb 17, 2005·Bioorganic & Medicinal Chemistry Letters·Bin ChenAlan P Kozikowski
Feb 18, 2005·Journal of Medicinal Chemistry·Claudia RosenbaumHerbert Waldmann
Apr 23, 2005·Toxicology and Applied Pharmacology·Elaine M LeslieSusan P C Cole
Apr 27, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Qin C RyanEdward A Sausville
May 18, 2005·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Roula Konsoula, Frank A Barile
Jun 16, 2005·Molecular Pharmacology·Milin R AcharyaWilliam D Figg
Jul 14, 2005·European Journal of Drug Metabolism and Pharmacokinetics·Shufeng ZhouJames W Paxton
Oct 8, 2005·Pharmacology & Therapeutics·Mikihisa TakanoTeruo Murakami
Jan 7, 2006·Nature Reviews. Cancer·Saverio Minucci, Pier Giuseppe Pelicci
Jun 20, 2008·International Journal of Pharmaceutics·Roula Konsoula, Mira Jung

❮ Previous
Next ❯

Citations

Feb 22, 2011·European Journal of Drug Metabolism and Pharmacokinetics·Yun-Xia LiCheng Peng
Dec 24, 2014·Molecular Pharmaceutics·Hyesik KongMilton L Brown
Oct 10, 2020·European Journal of Medicinal Chemistry·Maurício T TavaresSida Shen

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.