Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3

Uwai, Yuichi; Motohashi, Hideyuki; Tsuji, Yoshie; Ueo, Harumasa; Katsura, Toshiya; Inui, Kentaro

doi:10.1016/j.bcp.2007.03.024

Cited by 40 publications

(21 citation statements)

References 31 publications

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“…As shown in Figure 1, the apparent K m and V max values for hOAT1 and hOAT3 calculated in the present study were comparable to the results of several previous reports [26, 31-33]. In addition, the uptakes of [ 14 C]PAH and [ 3 H]ES were inhibited by probenecid (a typical inhibitor of OATs) in a concentration-dependent manner (Fig.…”

Section: Discussionsupporting

confidence: 92%

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers

et al. 2018

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Lansoprazole, a proton pump inhibitor, potently inhibits human organic anion transporter, hOAT3 (SLC22A8). Lansoprazole has an asymmetric atom in its structure and is clinically administered as a racemic mixture of (R)-and (S)-enantiomers. However, little is known about the stereoselective inhibitory potencies of lansoprazole against hOAT3 and its homolog, hOAT1. In the present study, the stereoselective inhibitory effect of lansoprazole was evaluated using hOAT1-and hOAT3-expressing cultured cells. hOAT1 and hOAT3 transported [¹⁴C]p-aminohippurate and [³H]estrone-3-sulfate (ES) with Michaelis-Menten constants of 29.8 ± 4.0 and 30.1 ± 9.0 µmol/L respectively. Lansoprazole enantiomers inhibited hOAT1- and hOAT3-mediated transport of each substrate in a concentration-dependent manner. The IC₅₀ value of (S)-lansoprazole against hOAT3-mediated transport of [³H]ES (0.61 ± 0.08 µmol/L) was significantly lower than that of (R)-lansoprazole (1.75 ± 0.31 µmol/L). In contrast, stereoselectivity was not demonstrated for the inhibition of hOAT1. Furthermore, (S)-lansoprazole inhibited hOAT3-mediated transport of pemetrexed and methotrexate (hOAT3 substrates) more strongly than the corresponding (R)-lansoprazole. This study is the first to demonstrate that the stereoselective inhibitory potency of (S)-lansoprazole against hOAT3 is greater than that of (R)-lansoprazole. The present findings provide novel information about the drug interactions associated with lansoprazole.

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Section: Discussionsupporting

confidence: 92%

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers

et al. 2018

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“…In agreement with our data, OAT1 was reported to mediate the transport of sulfated conjugates such as indoxyl sulfate [35], edaravone sulfate [16] and 5-sulfooxymethylfurfural [36]. Transport of more bulky glucuronidated metabolites by OAT1 was not observed [16,37]. Nonetheless, this study has also identified quercetin-3-O-glucuronide and quercetin-7-O-glucuronide as potential unique glucuronidated substrates of OAT1.…”

Section: Discussionsupporting

confidence: 91%

“…Nonetheless, this study has also identified quercetin-3-O-glucuronide and quercetin-7-O-glucuronide as potential unique glucuronidated substrates of OAT1. OAT3, on the other hand, has been shown to transport the sulfate or glucuronide conjugates, such as estrone-3-sulfate, edaravone sulfate, edaravone glucuronide [16], and 7-O-mycophenolic acid glucuronide [37]. Indeed, all the flavonoid conjugates tested herein showed significantly enhanced uptake in the OAT3-overexpressing cells, suggesting that OAT3 possesses a broader specificity for the flavonoid conjugates compared to OAT1.…”

Section: Discussionmentioning

confidence: 84%

Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6)

Wong

Botting

Orfila

et al. 2011

Biochemical Pharmacology

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. Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6). Biochemical Pharmacology, Elsevier, 2011, 81 (7) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 37A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 may be a mechanism of food-drug interaction via inhibition of renal uptake.

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“…11 mM) (Shen et al, 2015). Likewise, inhibition of DF-AG renal clearance mediated by OAT1 and OAT3 is unlikely, because CsA is not an inhibitor of either transporter (Uwai et al, 2007). Therefore, the DDI with CsA through the inhibition of renal transporters is unlikely.…”

Section: Discussionmentioning

confidence: 99%

Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro

Zhang

Han

Putluru

et al. 2015

Drug Metabolism and Disposition

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Although the metabolism and disposition of diclofenac (DF) has been studied extensively, information regarding the plasma levels of its acyl-b-D-glucuronide (DF-AG), a major metabolite, in human subjects is limited. Therefore, DF-AG concentrations were determined in plasma (acidified blood derived) of six healthy volunteers following a single oral DF dose (50 mg). Levels of DF-AG in plasma were high, as reflected by a DF-AG/DF ratio of 0.62 6 0.21 (C max mean 6 S.D.) and 0.84 6 0.21 (area under the concentration-time curve mean 6 S.D.). Both DF and DF-AG were also studied as substrates of different human drug transporters in vitro. DF was identified as a substrate of organic anion transporter (OAT) 2 only (K m = 46.8 mM). In contrast, DF-AG was identified as a substrate of numerous OATs (K m = 8.6, 60.2, 103.9, and 112 mM for OAT2, OAT1, OAT4, and OAT3, respectively), two organic aniontransporting polypeptides (OATP1B1, K m = 34 mM; OATP2B1, K m = 105 mM), breast cancer resistance protein (K m = 152 mM), and two multidrug resistance proteins (MRP2, K m = 145 mM; MRP3, K m = 196 mM). It is concluded that the disposition of DF-AG, once formed, can be mediated by various candidate transporters known to be expressed in the kidney (basolateral, OAT1, OAT2, and OAT3; apical, MRP2, BCRP, and OAT4) and liver (canalicular, MRP2 and BCRP; basolateral, OATP1B1, OATP2B1, OAT2, and MRP3). DF-AG is unstable in plasma and undergoes conversion to parent DF. Therefore, caution is warranted when assessing renal and hepatic transporter-mediated drug-drug interactions with DF and DF-AG.

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Interaction and transport characteristics of mycophenolic acid and its glucuronide via human organic anion transporters hOAT1 and hOAT3

Cited by 40 publications

References 31 publications

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers

Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6)

Diclofenac and Its Acyl Glucuronide: Determination of In Vivo Exposure in Human Subjects and Characterization as Human Drug Transporter Substrates In Vitro

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