Roles of organic cation transporters on the disposition of N-butylpyridinium chloride and structurally related ionic liquids

Persistent Link:
http://hdl.handle.net/10150/195472
Title:
Roles of organic cation transporters on the disposition of N-butylpyridinium chloride and structurally related ionic liquids
Author:
Cheng, Yaofeng
Issue Date:
2010
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Studies in this dissertation were conducted to explore the roles of organic cation transporters (OCTs) in the disposition of N-butylpyridinium Chloride (NBuPy-Cl) and structurally related ILs. Following a single i.v. dose to rats, the blood concentration of NBuPy-Cl and 1-butyl-1-methylpyrrolidinium chloride (BmPy-Cl) decreased in a biphasic manner with a clearance of 3.3 and 7 ml/min, respectively. More than 84% of dosed compounds were excreted in the urine. Depending on the vehicle, the dermal absorption of BmPy-Cl and NBuPy-Cl (5 mg/kg, 125 μg/cm²) was 10-35% at 96 h. Following a single oral (50 mg/kg) administration to rats, the maximum blood concentrations of both ILs were reached in less than 90 min in rats. Most of the orally dosed NBuPy-Cl (62-68 %) was excreted in the urine in 72 h. However, more of the dosed BmPy-Cl was eliminated in the feces Its oral bioavailability was only 47%. The elimination differences between BmPy-Cl and NBuPy-Cl were not altered by the size (0.5, 5, or 50 mg/kg) or frequency (1 or 5 administrations) of oral doses. In all urine and blood samples, only parent compounds were detected. Co-administration of NBuPy-Cl and inulin intravenously to rats revealed that the clearance of NBuPy-Cl exceeded the rat glomerular filtration rate, suggesting a renal secretion processing. The in vitro transport studies demonstrated that NBuPy-Cl, BmPy-Cl and 1-butyl-3-methylimidazolium chloride are substrates (Kt, 9~277 μM), as well as inhibitors (IC₅₀: 0.2~7.5 μM), of rOCT1/2 and hOCT2. Their inhibitory effects increased dramatically with increasing the alkyl chain length. The IC₅₀ values were 0.1, 3.8, 14 and 671 μM (hexyl-, butyl-, ethyl-pyridinium and pyridinium chloride) for rOCT2 mediated metformin transport. Similar structurally related inhibitory kinetics were observed for rOCT1 and hOCT2. In vivo co-administration of NBuPy-Cl prolonged the plasma half-life and reduced renal clearance of the diabetic drug, metformin. In summary, BmPy-Cl and NBuPy-Cl are partially absorbed from gastrointestinal tract. The present in blood is eliminated rapidly in the urine as parent, by renal filtration and OCT-mediated secretion. ILs also compete with other substrates of OCTs and have the potential to alter their pharmacokinetic profiles.
Type:
text; Electronic Dissertation
Keywords:
Ionic liquids; N-butylpyridinium chloride; organic cation transporters; pharmacokinetics; SAR; toxicity
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Medical Pharmacology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Sipes, I. Glenn
Committee Chair:
Sipes, I. Glenn

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleRoles of organic cation transporters on the disposition of N-butylpyridinium chloride and structurally related ionic liquidsen_US
dc.creatorCheng, Yaofengen_US
dc.contributor.authorCheng, Yaofengen_US
dc.date.issued2010en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractStudies in this dissertation were conducted to explore the roles of organic cation transporters (OCTs) in the disposition of N-butylpyridinium Chloride (NBuPy-Cl) and structurally related ILs. Following a single i.v. dose to rats, the blood concentration of NBuPy-Cl and 1-butyl-1-methylpyrrolidinium chloride (BmPy-Cl) decreased in a biphasic manner with a clearance of 3.3 and 7 ml/min, respectively. More than 84% of dosed compounds were excreted in the urine. Depending on the vehicle, the dermal absorption of BmPy-Cl and NBuPy-Cl (5 mg/kg, 125 μg/cm²) was 10-35% at 96 h. Following a single oral (50 mg/kg) administration to rats, the maximum blood concentrations of both ILs were reached in less than 90 min in rats. Most of the orally dosed NBuPy-Cl (62-68 %) was excreted in the urine in 72 h. However, more of the dosed BmPy-Cl was eliminated in the feces Its oral bioavailability was only 47%. The elimination differences between BmPy-Cl and NBuPy-Cl were not altered by the size (0.5, 5, or 50 mg/kg) or frequency (1 or 5 administrations) of oral doses. In all urine and blood samples, only parent compounds were detected. Co-administration of NBuPy-Cl and inulin intravenously to rats revealed that the clearance of NBuPy-Cl exceeded the rat glomerular filtration rate, suggesting a renal secretion processing. The in vitro transport studies demonstrated that NBuPy-Cl, BmPy-Cl and 1-butyl-3-methylimidazolium chloride are substrates (Kt, 9~277 μM), as well as inhibitors (IC₅₀: 0.2~7.5 μM), of rOCT1/2 and hOCT2. Their inhibitory effects increased dramatically with increasing the alkyl chain length. The IC₅₀ values were 0.1, 3.8, 14 and 671 μM (hexyl-, butyl-, ethyl-pyridinium and pyridinium chloride) for rOCT2 mediated metformin transport. Similar structurally related inhibitory kinetics were observed for rOCT1 and hOCT2. In vivo co-administration of NBuPy-Cl prolonged the plasma half-life and reduced renal clearance of the diabetic drug, metformin. In summary, BmPy-Cl and NBuPy-Cl are partially absorbed from gastrointestinal tract. The present in blood is eliminated rapidly in the urine as parent, by renal filtration and OCT-mediated secretion. ILs also compete with other substrates of OCTs and have the potential to alter their pharmacokinetic profiles.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectIonic liquidsen_US
dc.subjectN-butylpyridinium chlorideen_US
dc.subjectorganic cation transportersen_US
dc.subjectpharmacokineticsen_US
dc.subjectSARen_US
dc.subjecttoxicityen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMedical Pharmacologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorSipes, I. Glennen_US
dc.contributor.chairSipes, I. Glennen_US
dc.contributor.committeememberSipes, I. Glennen_US
dc.contributor.committeememberChen, Qinen_US
dc.contributor.committeememberWright, Stephen H.en_US
dc.contributor.committeememberCherrington, Nathanen_US
dc.contributor.committeememberStamer, W. Danielen_US
dc.identifier.proquest10838en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.