Stereoselective Inhibition of Methotrexate Excretion by Glucuronides of Nonsteroidal Anti-inflammatory Drugs via Multidrug Resistance Proteins 2 and 4

Kawase, Atsushi; Yamamoto, Taiki; Egashira, Sachiko; Iwaki, Masahiro

doi:10.1124/jpet.115.229104

Cited by 36 publications

(33 citation statements)

References 61 publications

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“…Diclofenac, and its acyl glucuronide, has been implicated as a substrate and inhibitor of both MRP1‐4 and OATP1A4 (Kawase et al. ; Zhang et al. ), which warrants further interrogation of NCS‐382 transport mechanisms.…”

Section: Discussionmentioning

confidence: 99%

A pharmacokinetic evaluation and metabolite identification of the GHB receptor antagonist NCS ‐382 in mouse informs novel therapeutic strategies for the treatment of GHB intoxication

Ainslie

Gibson

Vogel

2016

Pharmacol Res Perspect

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Gamma‐aminobutyric acid (GABA) is an endogenous inhibitory neurotransmitter and precursor of gamma‐hydroxybutyric acid (GHB). NCS‐382 (6,7,8,9‐tetrahydro‐5‐hydroxy‐5H‐benzo‐cyclohept‐6‐ylideneacetic acid), a known GHB receptor antagonist, has shown significant efficacy in a murine model of succinic semialdehyde dehydrogenase deficiency (SSADHD), a heritable neurological disorder featuring chronic elevation of GHB that blocks the final step of GABA degradation. NCS‐382 exposures and elimination pathways remain unknown; therefore, the goal of the present work was to obtain in vivo pharmacokinetic data in a murine model and to identify the NCS‐382 metabolites formed by mouse and human. NCS‐382 single‐dose mouse pharmacokinetics were established following an intraperitoneal injection (100, 300, and 500 mg/kg body weight) and metabolite identification was conducted using HPLC‐MS/MS. Kinetic enzyme assays employed mouse and human liver microsomes. Upon gaining an understanding of the NCS‐382 clearance mechanisms, a chemical inhibitor was used to increase NCS‐382 brain exposure in a pharmacokinetic/pharmacodynamic study. Two major metabolic pathways of NCS‐382 were identified as dehydrogenation and glucuronidation. The K m for the dehydrogenation pathway was determined in mouse (K m = 29.5 ± 10.0 μmol/L) and human (K m = 12.7 ± 4.8 μmol/L) liver microsomes. Comparable parameters for glucuronidation were >100 μmol/L in both species. Inhibition of NCS‐382 glucuronidation, in vivo, by diclofenac resulted in increased NCS‐382 brain concentrations and protective effects in gamma‐butyrolactone‐treated mice. These initial evaluations of NCS‐382 pharmacokinetics and metabolism inform the development of NCS‐382 as a potential therapy for conditions of GHB elevation (including acute intoxication & SSADHD).

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Section: Discussionmentioning

confidence: 99%

A pharmacokinetic evaluation and metabolite identification of the GHB receptor antagonist NCS ‐382 in mouse informs novel therapeutic strategies for the treatment of GHB intoxication

Ainslie

Gibson

Vogel

2016

Pharmacol Res Perspect

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“…15,33,34) Our recent study suggested that NSAIDs-Glu inhibit MRP2 and MRP4-mediated MTX efflux more strongly than parent NSAIDs. 25) However, the inhibitory effect of plasma NSAIDs-Glu on renal uptake of MTX via OATs and RFC-1 remains unclear. In the present study, we evaluated the inhibitory potencies of NSAIDs-Glu on MTX uptake via OAT1 and OAT3.…”

Section: Resultsmentioning

confidence: 99%

“…25) The IC 50 values of NSAIDs-Glu for MRP2-and MRP4-mediated MTX transport were summarized in Table 2. Although stereoselectivity was observed in the inhibitory effect of NSAIDs-Glu on MRPs-mediated MTX transport (R/S ratio=0.03-2.57) ( Table 2), it was not observed in the effect on OATs (R/S ratio=0.61-2.51) ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…23,24) Recently, our laboratory reported that NSAIDs-Glu, as well as parent NSAIDs, are involved in inhibition of urinary excretion of MTX via MRP2 and MRP4. 25) Since the IC 50 of NSAIDs-Glu for MTX transport via MRPs was lower than that of parent NSAIDs, our results suggested that NSAIDs-Glu likely contribute to elevating the plasma concentration of MTX. However, despite the fact that some NSAIDs-Glu, such as glucuronides of diclofenac and ibuprofen, are detected in plasma after administration of NSAIDs, 26,27) inhibitory effect of NSAIDs-Glu on renal MTX uptake transporter such as OATs and RFC-1 is poorly understood.…”

mentioning

confidence: 89%

“…28,29) β-1-O-glucuronides of NSAIDs were prepared biosynthetically in vitro from respective NSAIDs using rat liver microsomes according to the published method. 25,30) The purity of the glucuronides obtained was determined by HPLC at a UV wavelength of 254 nm, with the remaining fraction consisting of polar impurities that did not yield the respective parent drugs. The purities of the glucuronides were almost homogenous (diclofenac glucuronide, 99%; S-naproxen glucuronide, 100%; R-naproxen glucuronide, 98%; S-ibuprofen glucuronide, 100%; R-ibuprofen glucuronide, 94%; S-flurbiprofen glucuronide, 96%; R-flurbiprofen glucuronide, 100%).…”

mentioning

confidence: 99%

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Inhibition of Methotrexate Uptake <i>via</i> Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

Iwaki

Shimada

Irino

et al. 2017

Biological & Pharmaceutical Bulletin

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Combination therapy of non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate (MTX) sometimes triggers adverse effects, such as liver injury, renal failure, gastrointestinal disorders, and myelosuppression, owing to the reduction of MTX clearance. Previous reports have suggested that NSAIDs inhibit renal MTX uptake via organic anion transporters (OATs) and reduced folate transporter (RFC)-1 and efflux via multidrug resistance-associated proteins (MRPs). Recently, our laboratory found inhibitory effects of NSAIDs-glucuronide (NSAIDs-Glu), a major metabolite of NSAIDs, on MRP-mediated MTX transport as a new site of interaction between MTX and NSAIDs. However, it remains unclear that whether NSAIDsGlu inhibit renal uptake of MTX. Therefore, the present study aimed to evaluate inhibitory effects of several NSAIDs-Glu (diclofenac, R-and S-ibuprofen, R-and S-flurbiprofen, and R-and S-naproxen) on human OAT1 and OAT3-mediated MTX transport. In this study, [ 3 H]MTX uptake was observed by using human OAT1 and OAT3-overexpressing HEK293 cells in the presence or absence of NSAIDs-Glu. All examined NSAIDs-Glu exhibited concentration-dependent inhibitory effects on MTX uptake via OAT1 and OAT3. Our results indicated that NSAIDs-Glu are more potent (5-to 15-fold) inhibitors of OAT3 than OAT1. Moreover, stereoselective inhibitory effects of NSAIDs-Glu on OATs-mediated MTX uptake were not observed, unlike on MRPs-mediated transport. These findings suggest that inhibition of OAT1 and OAT3-mediated renal uptake of MTX by plasma NSAIDs-Glu may be one of the competitive sites underlying complex drug interaction between MTX and NSAIDs.Key words drug interaction; methotrexate; non-steroidal anti-inflammatory drug; glucuronide; organic anion transporter Although methotrexate (MTX) is often co-administered with non-steroidal anti-inflammatory drugs (NSAIDs) to patients suffering from rheumatoid arthritis and neoplastic diseases, several NSAIDs, such as ketoprofen, indomethacin, naproxen, and diclofenac, reduce MTX clearance. Thus, combined administration of MTX and NSAIDs can result in elevated plasma MTX concentrations and severe adverse effects, such as liver injury, renal failure, gastrointestinal disorders, and myelosuppression. [1][2][3][4][5] In fact, the MTX prescribers' information states that combined use of MTX and NSAIDs may increase plasma MTX concentrations and adverse effects.MTX is primarily excreted in urine via glomerular filtration and active tubular secretion in its unchanged form.6) At a clinical plasma concentration of MTX (0.2-10 µM), approximately 25% of renal clearance is excreted by glomerular filtration and the remaining 75% is excreted by active tubular secretion. 7)In the tubular secretory process, organic anion transporters (OAT) 1 and 3 and reduced folate carrier (RFC)-1 transport MTX from the blood across the basolateral membrane. [8][9][10][11] Multidrug resistance-related proteins (MRP) 2 and 4 and breast cancer-resistant protein (BCRP) transport MTX across the apical membrane into the urine w...

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Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients

Akutsu

Mino

Naito

et al. 2022

Eur J Clin Pharmacol

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Stereoselective Inhibition of Methotrexate Excretion by Glucuronides of Nonsteroidal Anti-inflammatory Drugs via Multidrug Resistance Proteins 2 and 4

Cited by 36 publications

References 61 publications

A pharmacokinetic evaluation and metabolite identification of the GHB receptor antagonist NCS ‐382 in mouse informs novel therapeutic strategies for the treatment of GHB intoxication

A pharmacokinetic evaluation and metabolite identification of the GHB receptor antagonist NCS ‐382 in mouse informs novel therapeutic strategies for the treatment of GHB intoxication

Inhibition of Methotrexate Uptake <i>via</i> Organic Anion Transporters OAT1 and OAT3 by Glucuronides of Nonsteroidal Anti-inflammatory Drugs

Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients

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