The Molecular Basis for Hepatobiliary Transport of Organic Cations and Organic Anions

Meijer, Dirk K. F.; Müller, Michael

doi:10.1007/0-306-46812-3_4

Cited by 9 publications

(4 citation statements)

References 208 publications

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“…4 and 5), the uptake clearance of D01-4582 was different between SD and CD rats. It is known that anion transporters (Oatps and organic anion transporters) are expressed on the sinusoidal membrane of rat hepatocytes (Meijer et al, 1999). Based on results of the LUI study and the isolated hepatocyte study, the overall activities of the transporters involved in the uptake of E217␤G and E-sul, typical substrates of Oatps, were suggested to be at similar levels in both SD and CD rats (Figs.…”

Section: Discussionmentioning

confidence: 98%

Marked Strain Differences in the Pharmacokinetics of an α₄β₁Integrin Antagonist, 4-[1-[3-Chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic Acid (D01-4582), in Sprague-Dawley Rats Are Associated with Albumin Genetic Polymorphism

Ito¹,

Takahashi²,

Sudo³

et al. 2006

J Pharmacol Exp Ther

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Strain differences in pharmacokinetics of an ␣ 4 ␤ 1 integrin antagonist, 4-[1-[3-chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]methoxybenzoic acid (D01-4582), in Sprague-Dawley rat strains (SD rat and CD rat) and their mechanism were investigated. Total plasma clearances of D01-4582 were 31.5 and 5.23 ml/min/kg in SD and CD rats, respectively. From in vivo studies, hepatic uptake process was thought to be involved in the strain differences. Differences in the uptake of D01-4582 by isolated hepatocytes prepared from the both strains were not observed when hepatocytes were incubated with simple buffer, but marked differences were observed when hepatocytes were incubated with plasma. When the dissociation constants (K d ) for the plasma protein binding of D01-4582 were examined in six rat strains, each strain was classified into two groups: a high-K d group, which included SD rats, Brown Norway rats, and Wistar rats; and a low-K d group, which included CD rats, Lewis rats, and Eisai hyperbilirubinemic rats. Since all rat strains in the low-K d group showed higher area under the concentration-time curve for D01-4582 than rats in the high-K d group, it was considered that the strain differences in the pharmacokinetics of D01-4582 were due to differences in the binding affinity. Purified albumin also showed strain differences in K d . The cDNA sequence of the albumin was analyzed, and 11 substitutions were observed. V238L and T293I were found only in the high-K d group, suggesting that these amino acid changes reduced the binding affinity of albumin for D01-4582. In conclusion, the strain differences in D01-4582 pharmacokinetics were suggested to be caused by an alteration in K d , associated with albumin genetic polymorphism.In the process of drug discovery and development, the properties of drug candidates are assessed and screened for their pharmacological, toxicological, and pharmacokinetic aspects. One important issue in the pharmacokinetic evaluation is the prediction of interindividual variabilities in plasma concentrations in humans. For this purpose, the metabolic pathway, elimination route, and their relevant proteins are characterized, because metabolism and membrane transport, in most cases, govern the plasma concentration profiles of a drug. Once the relevant protein, e.g., CYP3A4 or OATP1B1, has been identified, information on the frequency of the variants with reduced activity helps us to estimate the risk of the occurrence of interindividual variabilities (Sadee, 1998;Pirmohamed and Park, 2001;Tribut et al., 2002;Evans and McLeod, 2003). Animal models, such as knockout mice and naturally occurring deficient animals, are useful for demonstrating the importance of the protein in vivo. If pharmacokinetics differ in model animals compared with that in normal animals, the protein of interest would play an important role in vivo. In other words, pharmacokinetic differences in model animals would imply the possibility that interindiArticle, publication date, and...

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Section: Discussionmentioning

confidence: 98%

Marked Strain Differences in the Pharmacokinetics of an α₄β₁Integrin Antagonist, 4-[1-[3-Chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic Acid (D01-4582), in Sprague-Dawley Rats Are Associated with Albumin Genetic Polymorphism

Ito¹,

Takahashi²,

Sudo³

et al. 2006

J Pharmacol Exp Ther

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“…We also note that, although there is considerable functional overlap of the OC and OA transport processes expressed in the kidney and the liver (and gastrointestinal tract), we have limited our focus to those processes believed to play major roles in the transport of these compounds in renal cells. Readers are directed to reviews on organic electrolyte transport expressed in the liver (12,201,231,233,273,419,501) and other organs (14,157,220,224,311,398,547).…”

Section: Introductionmentioning

confidence: 99%

Molecular and Cellular Physiology of Renal Organic Cation and Anion Transport

Wright

Dantzler

2004

Physiological Reviews

374

332

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Organic cations and anions (OCs and OAs, respectively) constitute an extraordinarily diverse array of compounds of physiological, pharmacological, and toxicological importance. Renal secretion of these compounds, which occurs principally along the proximal portion of the nephron, plays a critical role in regulating their plasma concentrations and in clearing the body of potentially toxic xenobiotics agents. The transepithelial transport involves separate entry and exit steps at the basolateral and luminal aspects of renal tubular cells. It is increasingly apparent that basolateral and luminal OC and OA transport reflects the concerted activity of a suite of separate transport processes arranged in parallel in each pole of proximal tubule cells. The cloning of multiple members of several distinct transport families, the subsequent characterization of their activity, and their subcellular localization within distinct regions of the kidney now allows the development of models describing the molecular basis of the renal secretion of OCs and OAs. This review examines recent work on this issue, with particular emphasis on attempts to integrate information concerning the activity of cloned transporters in heterologous expression systems to that observed in studies of physiologically intact renal systems.

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“…OCTs interact with many drugs, including the H2 antagonist ranitidine (Bourdet et al, 2005), the antidiabetic drug metformin (Wang et al, 2002), and the anticancer drug oxaliplatin (Yokoo et al, 2007). The majority of OCT substrates are monovalent and comparatively small cations, the socalled type I organic cations (Meijer et al, 1999;Wright, 2005) as exemplified by the prototypical substrates tetraethylammonium (TEA) and the neurotoxin 1-methyl-4-phenylpyridinium (MPP ϩ ) (Koepsell et al, 2007). In a recent study, paraquat was identified as a substrate for hOCT2 (Chen et al, 2007).…”

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confidence: 99%

Transport of Dicationic Drugs Pentamidine and Furamidine by Human Organic Cation Transporters

Xin

Ju²,

Wu³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The antiparasitic activity of aromatic diamidine drugs, pentamidine and furamidine, depends on their entry into the pathogenic protozoa via membrane transporters. However, no such diamidine transporter has been identified in mammalian cells. The goal of this study is to investigate whether these dicationic drugs are substrates for human organic cation transporters (hOCTs, solute carrier family 22A1-3) and whether hOCTs play a role in their tissue distribution, elimination, and toxicity. Inhibitory and substrate activities of pentamidine and furamidine were studied in stably trans-

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The Molecular Basis for Hepatobiliary Transport of Organic Cations and Organic Anions

Cited by 9 publications

References 208 publications

Marked Strain Differences in the Pharmacokinetics of an α₄β₁Integrin Antagonist, 4-[1-[3-Chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic Acid (D01-4582), in Sprague-Dawley Rats Are Associated with Albumin Genetic Polymorphism

Marked Strain Differences in the Pharmacokinetics of an α₄β₁Integrin Antagonist, 4-[1-[3-Chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic Acid (D01-4582), in Sprague-Dawley Rats Are Associated with Albumin Genetic Polymorphism

Molecular and Cellular Physiology of Renal Organic Cation and Anion Transport

Transport of Dicationic Drugs Pentamidine and Furamidine by Human Organic Cation Transporters

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The Molecular Basis for Hepatobiliary Transport of Organic Cations and Organic Anions

Cited by 9 publications

References 208 publications

Marked Strain Differences in the Pharmacokinetics of an α4β1Integrin Antagonist, 4-[1-[3-Chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic Acid (D01-4582), in Sprague-Dawley Rats Are Associated with Albumin Genetic Polymorphism

Marked Strain Differences in the Pharmacokinetics of an α4β1Integrin Antagonist, 4-[1-[3-Chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic Acid (D01-4582), in Sprague-Dawley Rats Are Associated with Albumin Genetic Polymorphism

Molecular and Cellular Physiology of Renal Organic Cation and Anion Transport

Transport of Dicationic Drugs Pentamidine and Furamidine by Human Organic Cation Transporters

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Product

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Marked Strain Differences in the Pharmacokinetics of an α₄β₁Integrin Antagonist, 4-[1-[3-Chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic Acid (D01-4582), in Sprague-Dawley Rats Are Associated with Albumin Genetic Polymorphism

Marked Strain Differences in the Pharmacokinetics of an α₄β₁Integrin Antagonist, 4-[1-[3-Chloro-4-[N-(2-methylphenyl)-ureido]phenylacetyl]-(4S)-fluoro-(2S)-pyrrolidine-2-yl]-methoxybenzoic Acid (D01-4582), in Sprague-Dawley Rats Are Associated with Albumin Genetic Polymorphism