Characterization of the Disposition and Toxicokinetics of<i>N</i>-Butylpyridinium Chloride in Male F-344 Rats and Female B6C3F1 Mice and Its Transport by Organic Cation Transporter 2

Cheng, Yong; Wright, Stephen H.; Hooth, Michelle J.; Sipes, I. G.

doi:10.1124/dmd.108.022681

Cited by 22 publications

(34 citation statements)

References 33 publications

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“…There are two mammalian MATEs, MATE1 and MATE2-K. Human kidneys express both homologs, whereas rodent kidneys express only MATE1 (Terada et al, 2006). In several studies, we observed that three ILs, NBuPy-Cl, Bmim-Cl, and BmPy-Cl, were excreted rapidly in the urine of rats as the parent compounds (Sipes et al, 2008;Cheng et al, 2009;Knudsen et al, 2009). Because the rate of clearance from plasma exceeded the glomerular filtration rate, it was proposed that these three ILs, which are organic cations, undergo transport-mediated secretion.…”

Section: Discussionmentioning

confidence: 88%

“…Because N-butylpyridinium chloride (NBuPy-Cl), 1-methyl-3-butylimidazolium chloride (Bmim-Cl), and N-butyl-N-methylpyrrolidinium (BmPy-Cl) are starting materials for many other ILs, they were selected by the National Toxicology Program for investigation of their disposition, metabolism, and toxicity. In previous studies, we reported that these three compounds are absorbed (40 -70%) from the rodent gastrointestinal tract and then are widely distributed in rats (Sipes et al, 2008;Cheng et al, 2009;Knudsen et al, 2009). For the three ILs, the portion of the dose that became systemically available was eliminated exclusively in the urine as the parent compound.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the Inhibitory Effects ofN-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

Cheng¹,

Martinez-Guerrero²,

Wright³

et al. 2011

Drug Metab Dispos

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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 (BmPyCl), 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 M). 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 M (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.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Characterization of the Inhibitory Effects ofN-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

Cheng¹,

Martinez-Guerrero²,

Wright³

et al. 2011

Drug Metab Dispos

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“…The three cationic ILs selected by the National Toxicology Program as models for toxicological testing are substrates for renal secretion in rats and mice (Sipes et al, 2008;Cheng et al, 2009;Knudsen et al, 2009), and two of them (BmPy and NBuPy) are transported by the basolateral entry step in OC secretion in human renal proximal tubule, OCT2 Knudsen, et al, 2009). If the basolateral entry step in the secretion of ILs involves the passive, electrogenic uniporter, OCT2, the active step in renal secretion of ILs must reside in the luminal membrane.…”

Section: Discussionmentioning

confidence: 99%

Substrate-Dependent Inhibition of Human MATE1 by Cationic Ionic Liquids

Martinez-Guerrero

Wright

2013

J Pharmacol Exp Ther

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The multidrug and toxin extruders 1-and 2-K (MATE1 and MATE2-K) are expressed in the luminal membrane of renal proximal tubule cells and provide the active step in the secretion of molecules that carry a net positive charge at physiologic pH, so-called organic cations. The present study tested whether structurally distinct MATE substrates can display different quantitative profiles of inhibition when interacting with structurally distinct ligands. The tested ligands were three structurally similar cationic ionic liquids (ILs, salts in the liquid state: Nbutylpyridinium, NBuPy; 1-methyl-3-butylimidazolium, Bmim; and N-butyl-N-methylpyrrolidinium, BmPy). Uptake was measured using Chinese hamster ovary cells that stably expressed MATE1 or MATE2-K. By trans-stimulation, all three ILs were transported by both MATE transporters. The three ILs also inhibited uptake of three structurally distinct MATE substrates: 1-methyl-4-phenylpyridinium (MPP), triethylmethylammonium (TEMA), and N,N,N-trimethyl-2-[methyl(7-nitrobenzo[c][1,2, 5]oxadiazol-4-yl)amino]ethanaminium (NBD-MTMA). MATE1 displayed a higher affinity for the pyridinium-based NBuPy (IC 50 values, 2-4 mM) than for either the pyrrolidinium-(BmPy; 20-70 mM) or imidazolium-based ILs (Bmim; 15-60 mM). Inhibition of MPP, TEMA, and NBD-MTMA transport by NBuPy was competitive, with comparable K i values against all substrates. Bmim also competitively blocked the three substrates but with K i values that differed significantly (20 mM against MPP and 30 mM against NBD-MTMA versus 60 mM against TEMA). Together, these data indicate that renal secretion of ILs by the human kidney involves MATE transporters and suggest that the mechanism of transport inhibition is ligand-dependent, supporting the hypothesis that the binding of substrates to MATE transporters involves interaction with a binding surface with multiple binding sites.

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“…The rat hepatic blood flow (Q) was assumed to be 45 ml/min/kg (Corley et al, 2005), and f u was determined to be 0.6 by a method described previously by Cheng et al (2009). fu inc was estimated to be 0.94 (Hallifax and Houston, 2006).…”

Section: Methodsmentioning

confidence: 99%

In Vitro Glucuronidation of 2,2-Bis(bromomethyl)-1,3-propanediol by Microsomes and Hepatocytes from Rats and Humans

Rad

Hoehle²,

Kuester³

et al. 2010

Drug Metab Dispos

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ABSTRACT:2,2-Bis(bromomethyl)-1,3-propanediol (BMP) is a brominated flame retardant used in unsaturated polyester resins. In a 2-year bioassay BMP was shown to be a multisite carcinogen in rats and mice. Because glucuronidation is the key metabolic transformation of BMP by rats, in this study the in vitro hepatic glucuronidation of BMP was compared across several species. In addition, the glucuronidation activities of human intestinal microsomes and specific human hepatic UDP-glucuronosyltransferase (UGT) enzymes for BMP were determined. To explore other possible routes of metabolism for BMP, studies were conducted with rat and human hepatocytes. Incubation of hepatic microsomes with BMP in the presence of UDP-glucuronic acid resulted in the formation of a BMP monoglucuronide. The order of hepatic microsomal glucuronidation activity of BMP was rats, mice Ͼ Ͼ hamsters > monkeys humans. The rate of glucuronidation by rat hepatic microsomes was 90-fold greater than that of human hepatic microsomes. Human intestinal microsomes converted BMP to BMP glucuronide at a rate even lower than that of human hepatic microsomes. Among the human UGT enzymes tested, only UGT2B7 had detectable glucuronidation activity for BMP. BMP monoglucuronide was the only metabolite formed when BMP was incubated with suspensions of freshly isolated hepatocytes from male F-344 rats or with cryopreserved human hepatocytes. Glucuronidation of BMP in human hepatocytes was extremely low. Overall, the results support in vivo studies in rats in which BMP glucuronide was the only metabolite found. The poor glucuronidation capacity of humans for BMP suggests that the pharmacokinetic profile of BMP in humans will be dramatically different from that of rodents.

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Characterization of the Disposition and Toxicokinetics ofN-Butylpyridinium Chloride in Male F-344 Rats and Female B6C3F1 Mice and Its Transport by Organic Cation Transporter 2

Cited by 22 publications

References 33 publications

Characterization of the Inhibitory Effects ofN-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

Characterization of the Inhibitory Effects ofN-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

Substrate-Dependent Inhibition of Human MATE1 by Cationic Ionic Liquids

In Vitro Glucuronidation of 2,2-Bis(bromomethyl)-1,3-propanediol by Microsomes and Hepatocytes from Rats and Humans

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