Development and characterization of an immobilized human organic cation transporter based liquid chromatographic stationary phase

Moaddel, Ruin; Yamaguchi, Rika; Ho, Peiying; Patel, Sharvil; Hsu, Chyi‐Hung; Subrahmanyam, Vangala; Wainer, Irving W.

doi:10.1016/j.jchromb.2005.01.015

Cited by 26 publications

(49 citation statements)

References 13 publications

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“…The CMAC(hOCT1) column was created from cellular membrane fragments obtained from a stably transfected MDCK cell line that expresses hOCT1. The K i values obtained using the CMAC(hOCT(+)) column correlated with previously reported K i values obtained using cellular uptake techniques, r 2 =0.9363; p =0.0016 (Moaddel et al 2005b). …”

Section: Determination Of Stereoselective Ligand Interactions With Drsupporting

confidence: 86%

“…In the study of small molecule–drug transporter interactions, CMAC columns have been created from cell lines that stably express Pgp (Zhang et al 2000; Moaddel et al 2006), hOCT1 (Moaddel et al 2005b) and hOAT1 and 2 (Kimura et al 2007). These columns have been used in a variety of studies that are described below.…”

Section: Determination Of Stereoselective Ligand Interactions With Drmentioning

confidence: 99%

“…The development of a CMAC(hOCT1) column has recently been reported as an alternative approach to the determination of hOCT1 binding interactions (Moaddel et al 2005b). The CMAC(hOCT1) column was created from cellular membrane fragments obtained from a stably transfected MDCK cell line that expresses hOCT1.…”

Section: Determination Of Stereoselective Ligand Interactions With Drmentioning

confidence: 99%

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Determination and modelling of stereoselective interactions of ligands with drug transporters: A key dimension in the understanding of drug disposition

et al. 2008

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Stereochemistry is an important dimension in pharmacology and plays a role in every aspect of the pharmacological fate of chiral xenobiotics. This includes small molecule–drug transporter binding. This paper reviews the reported stereoselectivities of substrate and inhibitor interactions with P-glycoprotein and the organic cation transporter obtained using standard functional and binding studies, as well as data obtained from online cellular membrane affinity chromatography studies. The use of stereochemical data in quantitative structure–activity relationship (QSAR) and pharmacophore modelling is also addressed as is the effect of ignoring the fact that small molecule–drug transporter interactions take place in three-dimensional and asymmetric space.

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Section: Determination Of Stereoselective Ligand Interactions With Drsupporting

confidence: 86%

Section: Determination Of Stereoselective Ligand Interactions With Drmentioning

confidence: 99%

Section: Determination Of Stereoselective Ligand Interactions With Drmentioning

confidence: 99%

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Determination and modelling of stereoselective interactions of ligands with drug transporters: A key dimension in the understanding of drug disposition

et al. 2008

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“…Using a novel approach, by using a hOCT1 containing chromatographic column it has been shown that stereospecific binding to OCT was present for propranolol, atenolol and pseudoephedrine, with R:S binding ratios of 3.0, 2.1 and 1.53 being reported, respectively [77]. Using a similar approach, it was shown that R-verapamil bound to the hOCT1 receptor much more avidly than antipode, with a S:R ratio of 58 being reported in dissociation constant [78]. Stereoselectivity in OCT mediated transport, or its inhibition, by these agents is thereby possible.…”

Section: Excretionmentioning

confidence: 99%

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Brocks

2006

Biopharm. Drug Dispos.

134

108

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Many marketed drugs are chiral and are administered as the racemate, a 50:50 combination of two enantiomers. Pharmacodynamic and pharmacokinetic differences between enantiomers are well documented. Because of enantioselectivity in pharmacokinetics, results of in vitro pharmacodynamic studies involving enantiomers may differ from those in vivo where pharmacokinetic processes will proceed. With respect to pharmacokinetics, disparate plasma concentration vs time curves of enantiomers may result from the pharmacokinetic processes proceeding at different rates for the two enantiomers. At their foundation, pharmacokinetic processes may be enantioselective at the levels of drug absorption, distribution, metabolism and excretion. In some circumstances, one enantiomer can be chemically or biochemically inverted to its antipode in a unidirectional or bidirectional manner. Genetic consideration such as polymorphic drug metabolism and gender, and patient factors such as age, disease state and concomitant drug intake can all play a role in determining the relative plasma concentrations of the enantiomers of a racemic drug. The use of a nonstereoselective assay method for a racemic compound can lead to difficulties in interpretation of data from, for example, bioequivalence or dose/concentration vs effect assessments. In this review data from a number of representative studies involving pharmacokinetics of chiral drugs are presented and discussed.

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“…This laboratory previously developed an alternative method for the study of binding interactions between compounds and receptors or drug transporters [18,19]. This approach is based upon liquid chromatography utilizing stationary phases containing immobilized membranes from cells expressing the target protein.…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of immobilized human organic anion transporter-based liquid chromatographic stationary phase: hOAT1 and hOAT2

Kimura

Perry

Anzai

et al. 2007

Journal of Chromatography B

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This paper reports the development of liquid chromatographic columns containing immobilized organic anion transporters (hOAT1, hOAT2). Cellular membrane fragments from MDCK cells expressing hOAT1 and S2 cells expressing hOAT2 were immobilized on the surface of the immobilized artificial membrane (IAM) liquid chromatographic stationary phase. The resulting stationary phases were characterized by frontal affinity chromatography, using the marker ligand [ 3 H]-adefovir for the hOAT1 and [ 14 C]-p-aminohippurate for the hOAT2 in the presence of multiple displacers. The determined binding affinities (Kd) for eight OAT1 ligands and eight OAT2 ligands were correlated with literature values and a statistically significant correlation was obtained for both the hOAT1 and hOAT2 columns: r2= 0.688 (p < 0.05) and r2=0.9967 (p<0.0001), respectively. The results indicate that the OAT1 and OAT2 have been successfully immobilized with retention of their binding activity. The use of these columns to identify ligands to the respective transporters will be presented.

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Development and characterization of an immobilized human organic cation transporter based liquid chromatographic stationary phase

Cited by 26 publications

References 13 publications

Determination and modelling of stereoselective interactions of ligands with drug transporters: A key dimension in the understanding of drug disposition

Determination and modelling of stereoselective interactions of ligands with drug transporters: A key dimension in the understanding of drug disposition

Drug disposition in three dimensions: an update on stereoselectivity in pharmacokinetics

Development and characterization of immobilized human organic anion transporter-based liquid chromatographic stationary phase: hOAT1 and hOAT2

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