Methotrexate-Loxoprofen Interaction: Involvement of Human Organic Anion Transporters hOAT1 and hOAT3

Uwai, Yuichi; Taniguchi, Risa; Motohashi, Hideyuki; Saya, Hideyuki; Okuda, Masahiro; Inui, Ken Ichi

doi:10.2133/dmpk.19.369

Cited by 90 publications

(59 citation statements)

References 20 publications

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“…Our current results were also consistent with the findings of Lu et al (1999), who cloned hPAHT (p-aminohippurate transporter, the first name of hOAT1), which exhibited no significant MTX uptake activity. Uwai et al (2004) determined the K m value for hOAT1-mediated MTX uptake using a Xenopus laevis oocytes expression system to be 724 mM. In fact, this higher value of K m for hOAT1 supported our result, i.e., this concentration was not clinically relevant (Uwai et al, 2004).…”

Section: Discussionsupporting

confidence: 71%

“…Several drugs, including nonsteroidal anti-inflammatory drugs (Nozaki et al, 2007;Uwai et al, 2004;Maeda et al, 2008), penicillin G (Takeda et al, 2002b), and probenecid (Aherne et al, 1978), are known to inhibit the elimination of MTX. The molecular mechanism underlying these interactions partially relies on the blockade of the renal secretion of antifolate via the basal uptake transporters hOAT3 and hOAT1 (Giacomini et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

et al. 2014

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The coadministration of methotrexate (MTX) and proton pump inhibitors (PPIs) can result in a pharmacokinetic interaction that delays MTX elimination and subsequently increases the MTX blood concentrations. Human organic anion transporters (hOATs) are responsible for the renal tubular secretion of MTX and are thought to be involved in this drug interaction. The aim of this study was to evaluate the inhibitory potencies of PPIs on hOAT1 and hOAT3, which are the two isoforms of OATs predominantly expressed in kidney proximal tubules. Using stably transfected cell systems that express the uptake transporters human embryonic kidney (HEK)-hOAT1 and HEK-hOAT3, we analyzed the inhibitory potencies of omeprazole, lansoprazole, and pantoprazole on OAT-mediated [

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

et al. 2014

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“…A previous retrospective study demonstrated that the coadministration of NSAIDs was not a risk factor for the development of hematologic toxicity by pemetrexed (Sakata et al, 2013); however, NSAIDs are known as substrates and/or inhibitors of hOAT3 (Uwai et al, 2004;Nozaki et al, 2007). A clinical study has reported that a 20% increase in the area under the plasma concentration curve of pemetrexed was observed when 400 mg of ibuprofen was administered orally every 6 hours .…”

Section: Discussionmentioning

confidence: 99%

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

Ikemura

Hamada

Kaya

et al. 2016

Drug Metabolism and Disposition

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Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (K m = 68.3 6 11.1 mM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC 50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 6 0.17 mM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interactioninduced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.

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“…18,19) In addition, Deguchi et al reported no effect of 1 mM indomethacin on rOAT3, but the drug at 0.1 mM inhibited hOAT3 moderately. 20,21) Kynurenic acid and xanthurenic acid are closely related compounds. It is unique that rOAT3 showed similar transport activities for the two compounds, but that hOAT3 exhibited different.…”

Section: Discussionmentioning

confidence: 99%

Transport of Xanthurenic Acid by Rat/Human Organic Anion Transporters OAT1 and OAT3

Uwai

Honjo

2013

Bioscience, Biotechnology, and Biochemistry

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Kynurenic acid, a tryptophan metabolite, is involved in psychiatric disease. Our laboratory previously described its transport by rat/human organic anion transporters rOAT1, hOAT1, rOAT3 and hOAT3, which are involved in drug disposition. In this study, we performed an uptake experiment using Xenopus laevis oocytes to examine the transport of xanthurenic acid, a tryptophan catabolite and kynurenic acid analog, by various transporters. All the transporters tested stimulated the uptake of xanthurenic acid into oocytes. The transport activity of xanthurenic acid by hOAT1 was greater than that by rOAT1. In OAT3, the rat homolog showed efficient transport, compared with hOAT3. The apparent values of K m and V max for the transport by hOAT1 were 4.83 M and 26.0 pmol/ oocyte/h respectively. In rOAT3, the respective values were 6.87 M and 21.7 pmol/oocyte/h. This is the first report on xanthurenic acid transport by OAT1 and OAT3.

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Methotrexate-Loxoprofen Interaction: Involvement of Human Organic Anion Transporters hOAT1 and hOAT3

Cited by 90 publications

References 20 publications

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

Proton Pump Inhibitors Inhibit Methotrexate Transport by Renal Basolateral Organic Anion Transporter hOAT3

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3

Transport of Xanthurenic Acid by Rat/Human Organic Anion Transporters OAT1 and OAT3

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