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

Chioukh, Rym; Noël-Hudson, Marie-Sophie; Ribes, Sandy; Fournier, Natalie; Becquemont, Laurent; Verstuyft, Céline

doi:10.1124/dmd.114.058529

Cited by 50 publications

(38 citation statements)

References 50 publications

(58 reference statements)

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“…On the other hand, although NSAIDs showed mild inhibition of OCT-mediated uptake, the level of inhibition was minor. In contrast, extensive studies of omeprazole and lansoprazole have reported the inhibition of renal OATs and DDIs with methotrexate (a substrate of OATs) in vitro and in vivo (27,28). We also suspected similar drug interactions based on our in vitro data, which showed that omeprazole and lansoprazole inhibited OAT1-and OAT3-mediated PAS uptake by more than 70%.…”

Section: Figmentioning

confidence: 39%

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Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

Parvez

Shin

Jung

et al. 2017

Antimicrob Agents Chemother

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para-Aminosalicylic acid (PAS) is a second-line antituberculosis drug that has been used to treat multidrug-resistant and extensively drug-resistant tuberculosis for more than 60 years. Renal secretion and glomerular filtration are the major pathways for the elimination of PAS. We comprehensively studied PAS transport by using cell lines that overexpressed various transporters and found that PAS acts as a novel substrate of an organic anionic polypeptide (OATP1B1), organic cationic transporters (OCT1 and OCT2), and organic anion transporters (OAT1 and OAT3) but is not a substrate of any ATP-binding cassette (ABC) transporters. Net PAS uptake was measured, and the transport affinities (K m values) for OATP1B1, OCT1, OCT2, OAT1, and OAT3 were found to be 50.0, 20.3, 28.7, 78.1, and 100.1 M, respectively. The net uptake rates suggested that renal OAT1 and OAT3 play relatively major roles in PAS elimination. The representative inhibitors rifampin for OATP1B1, probenecid for OAT1 and OAT3, and verapamil for OCT1 and OCT2 greatly inhibited PAS uptake, suggesting that PAS is dependent on multiple transporters for uptake. We also evaluated nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and metformin for the inhibition of PAS uptake via these transporters. Half-maximal (50%) inhibitory concentrations (IC 50 s) were kinetically determined and used to predict the drug-drug interactions (DDIs) affecting these transporters' activity toward PAS. We found that rifampin, probenecid, ibuprofen, naproxen, cimetidine, and quinidine each exhibited a significant potential for in vivo DDIs with PAS. In this study, PAS was found to be a novel substrate of several transporters, and drugs that inhibit these transporters can reduce PAS elimination.

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Section: Figmentioning

confidence: 39%

“…For the OCTs and OATs, we simply calculated the drug-drug interaction index using the equation C max /IC 50 , where C max indicates the maximum concentration and C max,u indicates the maximum unbound concentration of the inhibitor present in the systemic circulation (27,33,(39)(40)(41).…”

Section: Methodsmentioning

confidence: 99%

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

Parvez

Shin

Jung

et al. 2017

Antimicrob Agents Chemother

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“…A recent study reported that hOAT3-mediated transport of methotrexate, which has a structure and pharmacokinetics similar to pemetrexed, was inhibited by PPIs (Chioukh et al, 2014). Several case reports and retrospective studies have demonstrated that coadministration of PPIs delayed the elimination of methotrexate (Suzuki et al, 2009;Santucci et al, 2010;Reeves et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…An estimated 20% of cancer patients have been treated with PPIs for alleviating the symptoms of gastroesophageal reflux (Smelick et al, 2013), highlighting the importance of investigating the drug interaction between PPIs and anticancer agents to provide safe and appropriate chemotherapy. Recent studies have reported that PPIs are inhibitors of hOATs and hOCTs (Nies et al, 2011;Chioukh et al, 2014). Since hematologic toxicity as a serious side effect of pemetrexed has been correlated with drug exposure (Rollins and Lindley, 2005), decreased clearance results in greater systemic exposure, which may be associated with increased side effects.…”

Section: Introductionmentioning

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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“…To relate our findings to clinical applications, we calculated the DDI index (22)(23)(24) according to the FDA guideline using the maximum concentration in plasma (C max ) and the unbound maximum concentration in plasma (C max,u ) (clinical pharmacokinetic data) (see Table S2 in the supplemental material) for each drug and the IC 50 for the prototype substrate and the clinically used substrate (zidovudine and metformin) from our in vitro study by plotting the equation mentioned in the FDA guideline and other reports to predict the possibility of a clinical DDI. Simply, we followed the method described by the FDA draft guidance and others: DDI index ϭ C max /IC 50 , where C max indicates the maximum concentration and C max,u indicates the maximum unbound concentration of the inhibitor present in the plasma (16,20,(23)(24)(25).…”

Section: Chemicalsmentioning

confidence: 99%

Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family

Parvez

Kaisar

Shin

et al. 2016

Antimicrob Agents Chemother

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b Twenty-two currently marketed antituberculosis drugs were comprehensively evaluated for their inhibitory effect on organic anionic transporter (OAT)-and organic cation transporter (OCT)-mediated uptake using stably transfected HEK293 cells in vitro. We observed moderate to strong inhibitory effects on OAT1-and OAT3-mediated para-aminohippurate (PAH) uptake and OCT1-and OCT2-mediated N-methyl-4-phenylpylidinium acetate (MPP ؉ ) uptake. Ciprofloxacin, linezolid, para-aminosalicylic acid (PAS), and rifampin were observed to have strong inhibitory effects, with the concentrations for a 50% inhibitory effect (IC 50 s) being 35.1, 31.1, 37.6, and 48.1 M, respectively, for OAT1 and >100, 21.9, 24.6, and 30.2 M, respectively, for OAT3. Similarly, pyrazinamide, rifabutin, and levofloxacin were observed to have inhibitory effects, with IC 50 values being 36.5, 42.7, and 30.3 M, respectively, for OCT1 and with the IC 50 value for PAS being 94.2 M for OCT2. In addition, we used zidovudine and metformin as clinically prescribed substrates of OATs and OCTs, respectively, and zidovudine and metformin uptake was also strongly inhibited by the antituberculosis drugs. Among the tested drugs, the highest drug-drug interaction (DDI) indexes were found for PAS, which were 9.3 to 13.9 for OAT1 and 12.0 to 17.7 for OAT3, and linezolid, which were 1.18 to 2.15 for OAT1 and 1.7 to 3.01 for OAT3. Similarly, the DDI indexes of pyrazinamide and levofloxacin were 0.57 and 0.30, respectively, for OCT1, and the DDI index of PAS was 3.8 for OCT2, suggesting a stronger possibility (DDI index value cutoff, >0.1) of in vivo DDIs. This is the first comprehensive report of the inhibitory potential of anti-TB drugs on OAT-and OCT-mediated uptake of prototype and clinically prescribed substrate drugs in vitro, providing an ability to predict DDIs between anti-TB drugs and other coprescribed drugs in clinical studies in vivo. So far, 400 human solute carrier family (SLC) transporter proteins have been identified as a superfamily and have been classified into 52 different subfamilies (1). The organic cation transporter (OCT; SLC22 subfamily) and organic anion transporter (OAT; SLC22 subfamily) families play a major role in the disposition and pharmacology of drug substances (2). Among these, organic cation transporter OCT1 (SLC22A1) appears to be highly expressed in the liver of all species and in many tissues, although intriguing differences between species have been noted. OCT1 expression is restricted to the basolateral membrane of proximal tubular cells, with the greatest expression being apparent in an early segment (segment S1) of superficial, midcortical, and juxtamedullary nephrons (3), whereas OCT2 (SLC22A2) is expressed in the kidney and appears to be restricted to the basolateral membrane of proximal tubular cells (4).The function of OCTs includes mediation of the transport of organic cations into or out of cells. Not all but many organic cations (of endogenous and exogenous origin) are substrates of OCTs. Endogenous organic cations includ...

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

Cited by 50 publications

References 50 publications

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

Evaluation of para -Aminosalicylic Acid as a Substrate of Multiple Solute Carrier Uptake Transporters and Possible Drug Interactions with Nonsteroidal Anti-inflammatory Drugs In Vitro

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

Inhibitory Interaction Potential of 22 Antituberculosis Drugs on Organic Anion and Cation Transporters of the SLC22A Family

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