scholarly journals Prediction of the Effects of Renal Impairment on Clearance for Organic Cation Drugs that Undergo Renal Secretion: A Simulation-Based Study

2018 ◽  
Vol 46 (5) ◽  
pp. 758-769 ◽  
Author(s):  
Kristin E. Follman ◽  
Marilyn E. Morris
Keyword(s):  
Renal Impairment ◽  
Organic Cation ◽  
Renal Secretion ◽  
Simulation Based

scholarly journals Multiple Drug Transporters Are Involved in Renal Secretion of Entecavir

2016 ◽  
Vol 60 (10) ◽  
pp. 6260-6270 ◽  
Author(s):  
Xi Yang ◽  
Zhiyuan Ma ◽  
Sisi Zhou ◽  
Yayun Weng ◽  
Hongmei Lei ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Organic Cation ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Multiple Drug ◽  
Renal Secretion ◽  
Renal Tubular Cells ◽  
Anion Transporter ◽  
Chronic Hepatitis B Virus ◽  
In Cells

ABSTRACTEntecavir (ETV) is a first-line antiviral agent for the treatment of chronic hepatitis B virus infection. Renal excretion is the major elimination path of ETV, in which tubular secretion plays the key role. However, the secretion mechanism has not been clarified. We speculated that renal transporters mediated the secretion of ETV. Therefore, the aim of our study was to elucidate which transporters contribute to the renal disposition of ETV. Our results revealed that ETV (50 μM) remarkably reduced the accumulation of probe substrates in MDCK cells stably expressing human multidrug and toxin efflux extrusion proteins (hMATE1/2-K), organic cation transporter 2 (hOCT2), and carnitine/organic cation transporters (hOCTNs) and increased the substrate accumulation in cells transfected with multidrug resistance-associated protein 2 (hMRP2) or multidrug resistance protein 1 (hMDR1). Moreover, ETV was proved to be a substrate of the above-described transporters. In transwell studies, the transport of ETV in MDCK-hOCT2-hMATE1 showed a distinct directionality from BL (hOCT2) to AP (hMATE1), and the cellular accumulation of ETV in cells expressing hMATE1 was dramatically lower than that of the mock-treated cells. The accumulation of ETV in mouse primary renal tubular cells was obviously affected by inhibitors of organic anion transporter 1/3 (Oat1/3), Oct2, Octn1/2, and Mrp2. Therefore, the renal uptake of ETV is likely mediated by OAT1/3 and OCT2 while the efflux is mediated by MATEs, MDR1, and MRP2, and OCTN1/2 may participate in both renal secretion and reabsorption.

Organic Cation Transporter-Mediated Renal Secretion of Ipratropium and Tiotropium in Rats and Humans

2010 ◽  
Vol 39 (1) ◽  
pp. 117-122 ◽  
Author(s):  
Takeo Nakanishi ◽  
Tsunemitsu Haruta ◽  
Yoshiyuki Shirasaka ◽  
Ikumi Tamai
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporter ◽  
Renal Secretion

scholarly journals Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins

2015 ◽  
Vol 43 (12) ◽  
pp. 1872-1881 ◽  
Author(s):  
Jia Yin ◽  
Haichuan Duan ◽  
Yoshiyuki Shirasaka ◽  
Bhagwat Prasad ◽  
Joanne Wang
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporter ◽  
Renal Secretion ◽  
Organic Cation Transporter 2 ◽  
Toxin Extrusion

Organic cation transporters 1 and 2 mediate pralidoxime renal secretion

2008 ◽  
Vol 180 ◽  
pp. S91
Author(s):  
Maya Kayouka ◽  
Pascal Houzé ◽  
Patricia Risède ◽  
Salvatore Cisternino ◽  
Frédéric Baud
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporters ◽  
Renal Secretion ◽  
Cation Transporters

scholarly journals Deficiency in the Organic Cation Transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in Mice Abolishes Renal Secretion of Organic Cations

2003 ◽  
Vol 23 (21) ◽  
pp. 7902-7908 ◽  
Author(s):  
Johan W. Jonker ◽  
Els Wagenaar ◽  
Sven van Eijl ◽  
Alfred H. Schinkel
Keyword(s):  
Organic Cation ◽  
Basolateral Membrane ◽  
Hepatic Uptake ◽  
The Body ◽  
Organic Cations ◽  
Organic Cation Transporters ◽  
Renal Secretion ◽  
Double Knockout ◽  
Intestinal Excretion ◽  
Cation Transporters

ABSTRACT The polyspecific organic cation transporters 1 and 2 (Oct1 and -2) transport a broad range of substrates, including drugs, toxins, and endogenous compounds. Their strategic localization in the basolateral membrane of epithelial cells in the liver, intestine (Oct1), and kidney (Oct1 and Oct2) suggests that they play an essential role in removing noxious compounds from the body. We previously showed that in Oct1 −/− mice, the hepatic uptake and intestinal excretion of organic cations are greatly reduced. Since Oct1 and Oct2 have extensively overlapping substrate specificities, they might be functionally redundant. To investigate the pharmacologic and physiologic roles of these proteins, we generated Oct2 single-knockout and Oct1/2 double-knockout mice. Oct2 −/− and Oct1/2 −/− mice are viable and fertile and display no obvious phenotypic abnormalities. Absence of Oct2 in itself had little effect on the pharmacokinetics of tetraethylammonium (TEA), but in Oct1/2 −/− mice, renal secretion of this compound was completely abolished, leaving only glomerular filtration as a TEA clearance mechanism. As a consequence, levels of TEA were substantially increased in the plasma of Oct1/2 −/− mice. This study shows that Oct1 and Oct2 together are essential for renal secretion of (small) organic cations. A deficiency in these proteins may thus result in increased drug sensitivity and toxicity.

Carnitine/Organic Cation Transporter OCTN2 (Slc22a5) Is Responsible for Renal Secretion of Cephaloridine in Mice

2009 ◽  
Vol 37 (5) ◽  
pp. 1009-1016 ◽  
Author(s):  
Takashi Kano ◽  
Yukio Kato ◽  
Kimihiro Ito ◽  
Takuo Ogihara ◽  
Yoshiyuki Kubo ◽  
...  
Keyword(s):  
Organic Cation ◽  
Organic Cation Transporter ◽  
Renal Secretion

A nucleoside-sensitive organic cation transporter in opossum kidney cells

1999 ◽  
Vol 276 (2) ◽  
pp. F323-F328 ◽  
Author(s):  
Rong Chen ◽  
Bih Fang Pan ◽  
Mamoru Sakurai ◽  
J. Arly Nelson
Keyword(s):  
Organic Cation ◽  
Rat Kidney ◽  
Organic Cation Transporter ◽  
Renal Secretion ◽  
Tetraethylammonium Bromide ◽  
Proximal Tubule Cells ◽  
Opossum Kidney ◽  
Opossum Kidney Cells ◽  
American Opossum ◽  
Active Processes

Renal secretion of organic cations and anions are pleiotropic, active processes in mammals. Some nucleosides such as deoxyadenosine (dAdo), 2-chlorodeoxyadenosine, and azidothymidine are secreted by human and rodent kidneys. Previous work (J. A. Nelson, J. F. Kuttesch, Jr., and B. H. Herbert. Biochemical Pharmacology 32: 2323–2327, 1983) indicated a role for the classic organic cation transporter (OCT) in the secretion of the dAdo analog, 2′-deoxytubercidin, by mouse kidney. Using [14C]tetraethylammonium bromide ([14C]TEA) as a substrate, we tested several renal cell lines for a nucleoside-sensitive OCT. American opossum kidney proximal tubule cells (OK) express a cimetidine-sensitive and metabolic-dependent ability to efflux TEA. Other classic OCT inhibitors and several nucleosides also inhibit TEA efflux by these cells in a manner reflecting structural specificity for the carrier. Inhibition of OCT by nucleosides is not a universal feature of OCTs, since TEA transport mediated by cloned rat kidney OCT2 in the Xenopus laevisoocyte system was not inhibited by the same nucleosides. In conclusion, OK cells appear to possess an OCT that may also transport some nucleosides by a novel carrier.

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