title: Characterization of the inhibitory effects of N-butylpyridinium chloride and structurally related ionic liquids on organic cation transporters 1/2 and human toxic extrusion transporters 1/2-k in vitro and in vivo.
abstract: Ionic liquids (ILs) are a class of salts that are expected to be used as a new source of solvents and for many other applications. Our previous studies revealed that selected ILs, structurally related organic cations, are eliminated exclusively in urine as the parent compound, partially mediated by renal transporters. This study investigated the inhibitory effects of N-butylpyridinium chloride (NBuPy-Cl) and structurally related ILs on organic cation transporters (OCTs) and multidrug and toxic extrusion transporters (MATEs) in vitro and in vivo. After Chinese hamster ovary cells expressing rat (r) OCT1, rOCT2, human (h) OCT2, hMATE1, or hMATE2-K were constructed, the ability of NBuPy-Cl, 1-methyl-3-butylimidazolium chloride (Bmim-Cl), N-butyl-N-methylpyrrolidinium chloride (BmPy-Cl), and alkyl substituted pyridinium ILs to inhibit these transporters was determined in vitro. NBuPy-Cl (0, 0.5, or 2 mg/kg per hour) was also infused into rats to assess its effect on the pharmacokinetics of metformin, a substrate of OCTs and MATEs. NBuPy-Cl, Bmim-Cl, and BmPy-Cl displayed strong inhibitory effects on these transporters (IC(50) = 0.2-8.5 μM). In addition, the inhibitory effects of alkyl-substituted pyridinium ILs on OCTs increased dramatically as the length of the alkyl chain increased. The IC(50) values were 0.1, 3.8, 14, and 671 μM (hexyl-, butyl-, and ethyl-pyridinium and pyridinium chloride) for rOCT2-mediated metformin transport. Similar structurally related inhibitory kinetics were also observed for rOCT1 and hOCT2. The in vivo coadministration study revealed that NBuPy-Cl reduced the renal clearance of metformin in rats. These results demonstrate that ILs compete with other substrates of OCTs and MATEs and could alter the in vivo pharmacokinetics of such substrates.
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ 85724-5050, USA.
authors.forename: Yaofeng
authors.initials: Y
authors.lastname: Cheng
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Martinez-Guerrero
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Wright
authors.forename: Robert K
authors.initials: RK
authors.lastname: Kuester
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Hooth
authors.forename: I Glenn
authors.initials: IG
authors.lastname: Sipes
mesh_terms: D000818:Animals; D016466:CHO Cells; D050482:Catecholamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D052578:Ionic Liquids / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000493:pharmacokinetics; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011726:Pyridinium Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D050482:Catecholamine Plasma Membrane Transport Proteins; D052578:Ionic Liquids; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D011726:Pyridinium Compounds; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; C521870:SLC47A2 protein, human; C493212:Slc22a1 protein, rat; C100590:Slc22a2 protein, rat; C046365:n-butylpyridinium; D008687:Metformin