Lumiracoxib Does Not Affect Methotrexate Pharmacokinetics in Rheumatoid Arthritis Patients

Hartmann, Stefan; Rordorf, Christiane; Milosavljev, Slavica; Branson, Janice; Chalès, Gérard; Juvin, R.; Lafforgue, P.; Parc, J. M. Le; Tavernier, C; Meyer, Olivier

doi:10.1345/aph.1e044

Cited by 27 publications

(20 citation statements)

References 23 publications

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“…This phenomenon was previously explained by the existence of two independent binding sites, one site that transports substrates and another site that can allosterically modulate the substrate transport site . Compounds that can stimulate as well as inhibit transport probably bind at low concentrations preferentially to the modulatory site, whereas at high concentrations, they can also compete for the Several NSAIDs belonging to the selective cyclooxygenase II inhibitors were reported not to affect the clinical pharmacokinetics of MTX (Schwartz et al, 2001;Hartmann et al, 2004), including celecoxib (Karim et al, 1999). This may be due to the low immunosuppressive MTX dosages used in these studies.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Nonsteroidal Anti-Inflammatory Drugs with Multidrug Resistance Protein (MRP) 2/ABCC2- and MRP4/ABCC4-Mediated Methotrexate Transport

El-Sheikh

Heuvel

Koenderink³

et al. 2006

J Pharmacol Exp Ther

202

150

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Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammatory diseases as well as malignancies. Especially at high MTX dosages, severe adverse effects with this combination may occur, usually resulting from an impaired renal elimination. It has been shown that the mechanism of this interaction cannot be fully attributed to inhibition of basolateral MTX uptake in renal proximal tubules. Here, we studied the effect of various NSAIDs on MTX transport in membrane vesicles isolated from cells overexpressing the proximal tubular apical efflux transporters human multidrug resistance protein (MRP) 2/ABCC2 and MRP4/ABCC4. MTX was transported by MRP2 and MRP4 with K m values of 480 Ϯ 90 and 220 Ϯ 70 M, respectively. The inhibitory potency of the NSAIDs was generally higher against MRP4-than MRP2-mediated MTX transport, with therapeutically relevant IC 50 values, ranging from approximately 2 M to 1.8 mM. Salicylate, piroxicam, ibuprofen, naproxen, sulindac, tolmetin, and etodolac inhibited MRP2-and MRP4-mediated MTX transport according to a one-site competition model. In some cases, more complex interaction patterns were observed. Inhibition of MRP4 by diclofenac and MRP2 by indomethacin and ketoprofen followed a two-site competition model. Phenylbutazone stimulated MRP2 and celecoxib MRP4 transport at low concentrations and inhibited both transporters at high concentration. Our data suggest that the inhibition by NSAIDs of renal MTX efflux via MRP2 and MRP4 is a potential new site and mechanism contributing to the overall interaction between these drugs.

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Section: Discussionmentioning

confidence: 99%

Interaction of Nonsteroidal Anti-Inflammatory Drugs with Multidrug Resistance Protein (MRP) 2/ABCC2- and MRP4/ABCC4-Mediated Methotrexate Transport

El-Sheikh

Heuvel

Koenderink³

et al. 2006

J Pharmacol Exp Ther

202

150

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“…92,93 Many cyclooxygenase-2 selective inhibitors such as lumiracoxib, rofecoxib, and celecoxib do not impact methotrexate pharmacokinetics. [94][95][96] Two additional drugs used for rheumatoid arthritis-leflunomide, a pyrimidine synthesis inhibitor, and anakinra, an interleukin 1 receptor antagonist-have been administered safely to patients taking methotrexate. 97,98 Other commonly prescribed drugs that have been given with methotrexate include a number of antibiotics.…”

Section: Drug Interactionsmentioning

confidence: 99%

Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference

Kalb

Strober

Weinstein

et al. 2009

Journal of the American Academy of Dermatology

302

355

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“…The effects of the selective cyclooxyganase-2 inhibitors on the disposition of methotrexate are therefore of interest. Although Hartmann et al reported no effect of lumiracoxib on the disposition of methotrexate in rheumatoid arthritis patients [7], we found that lumiracoxib inhibited human OAT1 (hOAT1) and hOAT3 strongly [8]. The goal of this study was to examine whether lumiracoxib influences renal OATs in vivo.…”

Section: Introductionmentioning

confidence: 78%

“…Hartmann et al conducted a clinical trial examining the effect of 7-day dosing of lumiracoxib at 400 mg/day on methotrexate pharmacokinetics, and observed no change [7]. In our study, 5 mg of lumiracoxib was injected into rats, and the dosage adjusted by the body weight was more than four times, compared with the report of Hartmann et al Accordingly, it is possible that overdose of lumiracoxib might delay elimination of drugs transported by OAT1 and OAT3 in a clinical situation.…”

Section: Resultsmentioning

confidence: 99%

Effect of selective cyclooxygenase-2 inhibitor lumiracoxib on phenolsulfonphthalein disposition in rats

Honjo¹,

Uwai²,

Nabekura³

2014

Drug Metabolism and Drug Interactions

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Selective cyclooxygenase-2 inhibitor lumiracoxib was shown to have the strong inhibitory potencies on the renal organic anion transporter (OAT)1 and also on OAT3 from drug transport experiments. The purpose of this study was to examine the effect of lumiracoxib on disposition of phenolsulfonphthalein (PSP) - which is mainly excreted into urine via OATs - from in vivo experiments. After the intravenous injection of PSP and lumiracoxib into rats, pharmacokinetic analysis was performed. After the intravenous injection of PSP as a bolus, its plasma concentration decreased time-dependently. Until 60 min after the injection, 51.1% of the dose was recovered into urine. The simultaneous administration of lumiracoxib increased the plasma levels of PSP and reduced its urinary recovery to 23.6% of the dose. The pharmacokinetic analysis using a two-compartment model exhibited that lumiracoxib affected the parameters implying the elimination of PSP. The present study demonstrates that lumiracoxib interfered with urinary excretion of PSP in rats.

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Lumiracoxib Does Not Affect Methotrexate Pharmacokinetics in Rheumatoid Arthritis Patients

Abstract: Lumiracoxib had no significant effect on the pharmacokinetics, protein binding, or urinary excretion of coadministered methotrexate in patients with RA.

Cited by 27 publications

References 23 publications

Interaction of Nonsteroidal Anti-Inflammatory Drugs with Multidrug Resistance Protein (MRP) 2/ABCC2- and MRP4/ABCC4-Mediated Methotrexate Transport

Interaction of Nonsteroidal Anti-Inflammatory Drugs with Multidrug Resistance Protein (MRP) 2/ABCC2- and MRP4/ABCC4-Mediated Methotrexate Transport

Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference

Effect of selective cyclooxygenase-2 inhibitor lumiracoxib on phenolsulfonphthalein disposition in rats

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