The pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans. Effect of cimetidine.

Vree, T. B.; Biggelaar-Martea, M. van den; Wissen, C.P.W.G.M. Verwey-van; Vree, M. L.; Guelen, P. J. M.

doi:10.1111/j.1365-2125.1993.tb04171.x

Cited by 49 publications

(38 citation statements)

References 29 publications

(30 reference statements)

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“…Although unbound plasma concentrations of NSAIDs-Glu have not been previously reported, total plasma concentrations of glucuronide conjugates of diclofenac (1.8±0.5 µM), 24) ibuprofen (3.6±2.0 µM), 23) naproxen (undetectable) 35) and flurbiprofen (undetectable) 36) have been determined after administration of clinical doses. Therefore, considering plasma concentration and inhibitory potencies, it is unlikely that NSAIDs-Glu other than diclofenac glucuronide inhibit OAT3-mediated MTX uptake at clinical doses.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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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“…Cimetidine has been shown to specifically increase the urinary excretion of naproxen acyl glucuronide, in contrast to other naproxen glucuronide metabolites (48).…”

Section: Xenobiotic Induction and Physiological Perturbation In Humansmentioning

confidence: 99%

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

Burchell

Coughtrie

1997

Environ Health Perspect

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Glucuronidation and sulfation are phase 2 metabolic reactions catalyzed by large families of different isoenzymes in man. The textbook view that glucuronidation and sulfation lead to the production of harmless conjugates for simple excretion is not valid. Biologically active and toxic sulfates and glucuronides are produced and lead to adverse drug reactions, including immune hypersensitivity. Considerable variation in xenobiotic conjugation is observed as a result of altered expression of UDP-glucuronosyltransferases (UGTs) and sulfotransferases (STs). Recent cloning and expression of human cDNA encoding UGTs and STs has facilitated characterization of isoform substrate specificity, which has been further validated using specific antibodies and human tissue fractions. The availability of cloned/expressed human enzymes and specific antibodies has enabled the investigation of xenobiotic induction and metabolic disruption leading to adverse responses. Genetic polymorphisms of glucuronidation and sulfation are known to exist although the characterization and assessment of the importance of these variations are hampered by appropriate ethical studies in man with suitable safe model compounds. Genetic analysis has allowed molecular identification of defects in well-known hyperbilirubinemias. However, full characterization of the specific functional roles of human UGTs and STs requires rigorous kinetic and molecular analyses of the role of each enzyme in vivo through the use of specific antibodies and inhibitors. This will lead to the better prediction of variation of xenobiotic glucuronidation and sulfation in man. Environ Health Perspect 1 05(Suppl 4): 739-747 (1997)

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“…1). DMN possesses both a carboxy and a phenolic functional group and has been shown to form acyl glucuronide (DMN-AG) and sulfate (DMN-S) conjugates (Kiang et al, 1989;Vanggard-Andersen and Hansen, 1992;Vree et al, 1993;Fig. 1).…”

mentioning

confidence: 99%

Conjugation of Desmethylnaproxen in the Rat—A Novel Acyl Glucuronide-Sulfate Diconjugate as a Major Biliary Metabolite

Jäggi¹,

Addison²,

King³

et al. 2002

Drug Metab Dispos

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This paper is available online at http://dmd.aspetjournals.org ABSTRACT:The nonsteroidal anti-inflammatory drug naproxen is primarily metabolized in humans by acyl glucuronidation to form naproxen acyl glucuronide and by O-dealkylation to form 6-O-desmethylnaproxen (DMN). DMN contains both carboxy and phenolic groups and has been shown to form acyl glucuronide and sulfate conjugates. This project aimed to investigate whether DMN formed a phenolic glucuronide and diglucuronide(s) (with both the carboxy and phenolic groups glucuronidated). Male Sprague-Dawley rats (300-350 g) with exteriorized bile flow were dosed i.v. with DMN at 50 mg/kg. Four major DMN-related peaks were detected in bile by high-performance liquid chromatography (HPLC) analysis at 225 nm, including the known acyl glucuronide and sulfate conjugates. Selective hydrolyses using acidic and alkaline conditions and digestion with ␤-glucuronidase allowed tentative identification of the two unknown peaks as the phenolic glucuronide of DMN and a novel acyl glucuronide-sulfate diconjugate of DMN (i.e., formed by sulfonation of the phenolic group and glucuronidation of the carboxy group). The identities were confirmed by liquid chromatography-tandem mass spectrometry analysis of individual HPLC fractions. Total recovery of the DMN dose was approximately 80%, with the sulfate conjugate (50%) and unchanged DMN (10%) being excreted predominantly in urine and the acyl glucuronide (10%), phenolic glucuronide (6%), and acyl glucuronide-sulfate diconjugate (4%) being excreted predominantly or exclusively in bile. No evidence for a diglucuronide metabolite of DMN was found in either bile or urine of the DMN-dosed rats.The salicylate derivative diflunisal, a nonsteroidal anti-inflammatory drug (NSAID 1 ), has both carboxy and phenolic functional groups and forms acyl glucuronide, phenolic glucuronide, and sulfate monoconjugates as major metabolites in humans and animals (Tocco et al., 1975;Lin et al., 1985;Loewen et al., 1986;Dickinson et al., 1989). In previous work, we have reported the additional formation of small quantities of quasi "diglucuronides" of diflunisal in the rat and the perfused rat liver (King and Dickinson, 1991;Wang and Dickinson, 1998). The yield of diglucuronides was greater if the preformed biosynthetic acyl glucuronide was administered and much greater again when the acyl migration rearrangement isomers were administered. By contrast, no diglucuronides were formed after administration of the phenolic glucuronide of diflunisal. Interestingly, the mixture of diglucuronides appeared to comprise the phenolic glucuronides of the 2-, 3-, and possibly 4-O-positional isomers of the acyl glucuronides (King and Dickinson, 1991). Whether any "real" diglucuronide (i.e., the phenolic glucuronide of the biosynthetic acyl glucuronide) was formed was equivocal. These results brought forth interesting questions about the presence of recognition/transport/metabolism processes pertaining to real (i.e., biosynthetic) acyl glucuronides versus "look-alikes" (i.e...

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The pharmacokinetics of naproxen, its metabolite O‐desmethylnaproxen, and their acyl glucuronides in humans. Effect of cimetidine.

Cited by 49 publications

References 29 publications

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

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

Genetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation.

Conjugation of Desmethylnaproxen in the Rat—A Novel Acyl Glucuronide-Sulfate Diconjugate as a Major Biliary Metabolite

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