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Experimental observations on flufenamic, mefenamic and meclofenamic acids—III. Metabolic disposition
... 8 A proposed mechanism for the development of these toxicities suggests that MFA is metabolized to chemically-reactive metabolites that become covalently bound to tissue proteins leading to adverse immunological responses ( Figure 1). In addition to the cytochrome P450 mediated formation of the 3-hydroxy-MFA 9 and the 3-carboxy-MFA 10 , MFA is metabolized into the MFA-1-O-acyl-glucuornide (MFA-1-O-G), an unstable and reactive acyl glucuronide metabolite 8 capable of covalently binding onto human serum albumin 11 and thus may be implicated in MFA mediated idiosyncratic toxicity. Acyl glucuronides of acidic drugs are proposed to bind covalently to protein via two different mechanisms. ...
... MFA is metabolized by cytochrome P450 into the 3-hydroxymethyl-MFA that can either undergo glucuronidation or become further oxidized into the 3-carboxy-MFA, which is primarily excreted unchanged as a monoglucuronide. 9 In order to characterize the conjugative bioactivation products of MFA, it is preferable to use authentic standards. Therefore our initial efforts were dedicated to the synthesis of MFA-AMP, MFA-CoA, and MFA-GSH. ...
... MFA also undergoes direct conjugative metabolism via the free carboxyl group into the 1-O-acyl glucuronide, MFA-1-O-G, in vitro and in vivo (Figure 1).9,10 Studies have shown that MFA-1-O-G irreversibly binds to human serum albumin in vitro and that covalent binding to cellular proteins in culture occurs during the incubation of MFA in the heterologous Chinese hamster lung fibroblast cell line V79 over-expressing UGT1A2.11 ...
Mefenamic acid, (MFA), a carboxylic acid-containing nonsteroidal anti-inflammatory drug (NSAID), is metabolized into the chemically reactive conjugates MFA-1-O-acyl-glucuronide (MFA-1-O-G) and MFA-S-acyl-CoA (MFA-CoA), which are both implicated in the formation of MFA-S-acyl-glutathione (MFA-GSH) conjugates, protein-adduct formation, and thus the potential toxicity of the drug. However, current studies suggest that an additional acyl-linked metabolite may be implicated in the formation of MFA-GSH. In the present study, we investigated the ability of MFA to become bioactivated into the acyl-linked metabolite, mefenamyl-adenylate (MFA-AMP). In vitro incubations in rat hepatocytes with MFA (100 μM), followed by LC-MS/MS analyses of extracts, led to the detection of MFA-AMP. In these incubations, the initial rate of MFA-AMP formation was rapid, leveling off at a maximum concentration of 90.1 nM (20 s), while MFA-GSH formation increased linearly, reaching a concentration of 1.7 μM after 60 min of incubation. In comparison, MFA-CoA was undetectable in incubation extracts until the 4 min time point, achieving a concentration of 45.6 nM at the 60 min time point, and MFA-1-O-G formation was linear, attaining a concentration of 42.2 μM after 60 min of incubation. In vitro incubation in buffer with the model nucleophile glutathione (GSH) under physiological conditions showed MFA-AMP to be reactive toward GSH, but 11-fold less reactive than MFA-CoA, while MFA-1-O-G exhibited little reactivity. However, in the presence of glutathione-S-transferase (GST), MFA-AMP mediated formation of MFA-GSH increased 6-fold, while MFA-CoA mediated formation of MFA-GSH only increased 1.4-fold. Collectively, in addition to the MFA-1-O-G, these results demonstrate that mefenamic acid does become bioactivated by acyl-CoA synthetase enzyme(s) in vitro in rat hepatocytes into the reactive transacylating derivatives MFA-AMP and MFA-CoA, both of which contribute to the transacylation of GSH and may be involved in the formation of protein adducts and potentially elicit an idiosyncratic toxicity.
... Ponstel may prolong prothrombin time. 4 Therefore, when the drug is administered to patients receiving oral anticoagulant drugs, frequent monitoring of prothrombin time is necessary. ...
... For the relief of acute pain in adults and adolescents > 14 years of age, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours as needed, usually not to exceed one week. 4 For the treatment of primary dysmenorrhea, the recommended dose is 500 mg as an initial dose followed by 250 mg every 6 hours, given orally, starting with the onset of bleeding and associated symptoms. Clinical studies indicate that effect treatment can be initiated with the start of menses and should not be necessary for more than 2 to 3 days. ...
The development of a meaningful dissolution procedure for drug products with limited water solubility has been a challenge to both the pharmaceutical industry and the agencies that regulate them. On the other hand, poorly soluble drugs present a big problem in pharmaceutical formulations. Therefore, various methods to improve the dissolution of poorly soluble drugs have been reported and employing surfactants for this purpose is the leading approach. In spite of wide applications of Mefenamic acid, the enhancement of its solubility in water using surfactant systems has not been explored. Therefore, we have investigated the interaction between this drug and anionic (SDS, SDBS, DTAB, CTAB, TTAB) surfactants as well as non-ionic (Tween 20, Tween 40, Tween 60, Tween 80, Brij 30, Brij 35,Brij 56 and Brij 58) surfactants. The results show that, irrespective of the surfactant type, the solubility of Mefenamic acid increases with increase in concentration of a surfactant, leading to the conclusion that there is an association between the drug and the surfactants. The molar solubilization ratio, micelle–water partition coefficient (K
M), binding constant (K) and the Gibbs energy of solubilization () of the drug in the micelles were determined to yield a model to correlate the solubility with the structure of the surfactant used. An outcome of the results is that the order of solubility of this drug in non-ionic and ionic surfactants is Tween 80 > Tween 60 > Tween 40 > Tween 20 and, in the case of the Brij series, is Brij56 > Brij58 > Brij35 > Brij30, while in cationic and anionic surfactants the order is CTAB > TTAB > DTAB and SDBS > SDS.
... A proposed mechanism for the occurrence of these MFA-induced toxicities suggests that MFA undergoes bioactivation into chemicallyreactive acyl-linked metabolites that ultimately become covalently bound to tissue proteins, resulting in adverse immunologic responses (Fig. 1). MFA is metabolized to 3-hydroxy-MFA (Glazko, 1966) and 3-carboxy-MFA (Sato et al., 1993) via CYP 2C9. MFA also undergoes glucuronidation via uridine 59-diphospho-glucuronosyltransferase (UGT) into the unstable, reactive acyl glucuronide metabolite MFA-1-O-acyl-glucuronide (MFA-1-O-G) (McGurk et al., 1996;Somchit et al., 2004). ...
... These toxicities are proposed to occur via bioactivation of MFA into reactive acyl-linked metabolites covalently binding onto macromolecules. MFA undergoes conjugation via the free carboxyl group into the 1-O-acyl glucuronide, MFA-1-O-G (Glazko, 1966;Sato et al., 1993), which has been shown to irreversibly bind to albumin (McGurk et al., 1996). MFA also undergoes further conjugation into MFA-AMP, MFA-CoA, and MFA-GSH (Grillo et al., 2012;Horng and Benet, 2013) in rat hepatocytes, all of which possess an increased chemical electrophilicity and are reactive toward protein nucleophiles. ...
Mefenamic acid, (MFA), a carboxylic acid-containing nonsteroidal anti-inflammatory drug (NSAID) is metabolized into the chemically-reactive, MFA-1-O-acyl-glucuronide (MFA-1-O-G), MFA-acyl-adenylate (MFA-AMP), and the MFA-S-acyl-CoA (MFA-CoA), all of which are electrophilic and capable of acylating nucleophilic sites on biomolecules. In this study, we investigate the non-enzymatic ability of each MFA acyl-linked metabolite to transacylate amino and thiol functional groups on the acceptor biomolecules glycine (Gly), taurine (Tau), glutathione (GSH), and N-acetylcysteine (NAC). In vitro incubations with each of the MFA acyl-linked metabolites (1 μM) in buffer under physiological conditions with Gly, Tau, GSH, or NAC (10 mM) revealed that MFA-CoA was 11.5- and 19.5-fold more reactive than MFA-AMP towards the acylation of cysteine-sulfhydryl groups of GSH and NAC, respectively. However, MFA-AMP was more reactive towards both Gly and Tau, 17.5-fold more reactive towards the N-acyl-amidation of taurine than its corresponding CoA thioester, while MFA-CoA displayed little reactivity towards glycine. Additionally, MFA-GSH was 5.6- and 108-fold more reactive towards NAC than MFA-CoA and MFA-AMP, respectively. In comparison to MFA-AMP and MFA-CoA, MFA-1-O-G was not significantly reactive towards all four bionucleophiles. MFA-AMP, MFA-CoA, MFA-1-O-G, MFA-GSH, and MFA-Tau were also detected in rat in vitro hepatocyte MFA (100 μM) incubations while MFA-Gly was not. These results demonstrate that MFA-AMP selectively reacts nonenzymatically with the amino functional groups of glycine and lysine, MFA-CoA selectively reacts nonenzymatically with the thiol functional groups of GSH and NAC, and MFA-GSH reacts nonenzymatically with the thiol functional group of GSH, all of which may potentially elicit an idiosyncratic toxicity in vivo.
... The selective block of PGF2,-induced contractions of human gastrointestinal longitudinal muscle by sodium meclofenamate or flufenamate occurred with concentrations (1 and 2 pg/ml respectively) within therapeitic plasma levels. Glazko (1967) reported that in normal subjects a single oral dose of 200 mg flu- or albumin-bound drug. In contrast, mefenamic acid or its sodium salt did not selectively affect PGF2,-induced contractions, and the tendency for high concentrations (50 1ig/ml) to reduce contractions to PGE2 seems therapeutically unimportant since this amount exceeds the maximum plasma concentration of 'free' drug (approximately 10 pg/ml) following a single oral dose of 1 g mefenamic acid (Glazko, 1967). ...
... Glazko (1967) reported that in normal subjects a single oral dose of 200 mg flu- or albumin-bound drug. In contrast, mefenamic acid or its sodium salt did not selectively affect PGF2,-induced contractions, and the tendency for high concentrations (50 1ig/ml) to reduce contractions to PGE2 seems therapeutically unimportant since this amount exceeds the maximum plasma concentration of 'free' drug (approximately 10 pg/ml) following a single oral dose of 1 g mefenamic acid (Glazko, 1967). ...
Low concentrations of meclofenamate, flufenamate or mefenamate had little effect on contractions in response to acetylcholine in any tissue studied.
Sodium meclofenamate potently antagonized contractions of guinea‐pig ileum longitudinal muscle to prostaglandin E 2 (PGE 2 ), PGF 2α or PGD 2 .
In guinea‐pig colonic longitudinal muscle, contractions to PGE 2 were reduced by sodium meclofenamate, but contractions of the longitudinal or circular muscle to PGF 2α or PGD 2 were less effectively inhibited.
In human gastrointestinal longitudinal muscle, sodium meclofenamate or flufenamate potently inhibited contractions to PGF 2α , but not to PGE 2 .
Sodium mefenamate or mefenamic acid, even in high concentrations, had little effect on contractions to PGF 2α , but tended to inhibit PGE 2 ‐induced contractions of human gastrointestinal longitudinal muscle.
The therapeutic advantages of prostaglandin synthesis inhibitors which also antagonize responses to certain prostaglandins are discussed.
... The fenamic acids commonly used in pharmacy are mefenamic, tolfenamic, flufenamic, and meclofenamic acid. The clinical action and effectiveness of tolfenamic acid are known in the treatment of migraines [8], dysmenorrhea [9], as well as in rheumatic diseases [10,11]. All fenamic acids have undesired side effects; therefore, the simplest compound in this groupfenamic acid-is out of therapeutic application. ...
A new coordination compound of copper(II) with a tolfenamate ligand of the paddle-wheel-like structure [CuII2(Tolf)4(MeOH)2]∙2MeOH was obtained and structurally characterized. Chemical bonds of Cu(II)∙∙∙Cu(II) and Cu(II)–O were theoretically analyzed and compared with the results for selected similar structures from the CSD database. QTAIM analysis showed that the Cu(II)∙∙∙Cu(II) interaction has a strength comparable to a hydrogen bond, as indicated by the electron density at a critical point. The remaining QTAIM parameters indicate stability of the Cu(II)∙∙∙Cu(II) interaction. Other methods, such as NCI and NBO, also indicate a significant strength of this interaction. Thus, the Cu(II)∙∙∙Cu(II) interaction can be treated as one of the noncovalent interactions that affects the structure of the coordination compound, the packing of molecules in the crystal, and the general properties of the compound.
... Mefenamic acid is a member of the anthracitic acid derivatives class of NSAID drugs, and is used to treat mild to moderate pain, including menstrual pain, and is sometimes used to prevent migraines associated with menstruation It isn't widely used in the United States due to its side effects (1)(2)(3)(4). Its name derives from its systematic name, dimethyl phenyl amino benzoic acid ( fig. 1) It was discovered and brought to market by Parke-Davis in the 1960s. ...
A new, simple, sensitive and fast method for the determination of Mefenamic acid in pure form and drugs (tablets) by continuous flow injection analysis via measurement of diverged beam of light by ISNAG_-fluorimeter. The method based on the reaction of the Mefenamic acid with sodium persulfate to form yellow precipitate. Optimum parameter have been studied to increase the sensitivity for the developed method. The linear dynamic range for the instrument response versus Mefenamic acid concentration was 0.01-5 mmol/L while the L.O.D was 215.955 ng/sample from the step wise dilution for the minimum concentration of lowest concentration in the linear dynamic range of the calibration graph. The correlation coefficient (r) was 0.9968 while percentage linearity (R2%) was 99.35%. RSD% for the repeatability (n=8) was lower than 0.2% for the determination of Mefenamic acid, with concentration of 1, 3 mmol/L respectively. The: developed method was applied successfully for the determination of Mefenamic acid in pharmaceutical tablets. A comparison was made between the newly developed methodology and the classical method (turbidometry) of analysis using the standard addition method via the use of paired t-test. It shows that there was no significant difference between the quoted values of each individual company with calculated t-value at 95% confidence interval from developed method. Keyword: Mefenamic acid, flow injection analysis, diverged beam of light, homemade instrument.
... Mefenamic acid is a member of the anthracitic acid derivatives class of NSAID drugs, and is used to treat mild to moderate pain, including menstrual pain, and is sometimes used to prevent migraines associated with menstruation It isn't widely used in the United States due to its side effects (1)(2)(3)(4). Its name derives from its systematic name, dimethyl phenyl amino benzoic acid ( fig. 1) It was discovered and brought to market by Parke-Davis in the 1960s. ...
A new, simple, sensitive and fast method for the determination of Mefenamic acid in pure form and drugs (tablets) by continuous flow injection analysis via measurement of diverged beam of light by ISNAG_-fluorimeter. The method based on the reaction of the Mefenamic acid with sodium persulfate to form yellow precipitate. Optimum parameter have been studied to increase the sensitivity for the developed method. The linear dynamic range for the instrument response versus Mefenamic acid concentration was 0.01-5 mmol/L while the L.O.D was 215.955 ng/sample from the step wise dilution for the minimum concentration of lowest concentration in the linear dynamic range of the calibration graph. The correlation coefficient (r) was 0.9968 while percentage linearity (R2%) was 99.35%. RSD% for the repeatability (n=8) was lower than 0.2% for the determination of Mefenamic acid, with concentration of 1, 3 mmol/L respectively. The: developed method was applied successfully for the determination of Mefenamic acid in pharmaceutical tablets. A comparison was made between the newly developed methodology and the classical method (turbidometry) of analysis using the standard addition method via the use of paired t-test. It shows that there was no significant difference between the quoted values of each individual company with calculated t-value at 95% confidence interval from developed method. Keyword: Mefenamic acid, flow injection analysis, diverged beam of light, homemade instrument.
... Mefenamic acid is a member of the anthracitic acid derivatives class of NSAID drugs, and is used to treat mild to moderate pain, including menstrual pain, and is sometimes used to prevent migraines associated with menstruation It isn't widely used in the United States due to its side effects (1)(2)(3)(4). Its name derives from its systematic name, dimethyl phenyl amino benzoic acid ( fig. 1) It was discovered and brought to market by Parke-Davis in the 1960s. ...
A new, simple, sensitive and fast method for the determination of Mefenamic acid in pure form and drugs (tablets) by continuous flow feed analysis via measurement of diverged beam of light by ISNAG_-fluorimeter (homemade instrument). The method based on the reaction of the Mefenamic acid with 8-HQ to form yellow precipitate. Optimum parameters have been studied to increase the sensitivity for the developed method. The linear dynamic range for the instrument response versus Mefenamic acid concentration was 0.005-7 mmol/L while the L.O.D was 0.216 µg/sample from the step wise dilution for the minimum concentration of lowest concentration in the linear dynamic range of the calibration graph. The correlation coefficient (r) was 0.9956 while percentage linearity (R 2 %) was 99.12%. RSD % for the repeatability (n=8) was lower than 0.2% for the determination of Mefenamic acid, with concentration of 2, 5 mmol/L respectively. The developed method was applied successfully for the determination of Mefenamic acid in pharmaceutical tablets. A comparison was made between the newly developed method with the classical method (UV-Vis spectrophotometry at wavelength 285nm, and Turbidemtric method) of analysis using the standard addition method via the use of paired t-test. It shows that there was no significant difference between the quoted values of each individual company with calculated t-value at 95% confidence interval from developed method.
... As an advantage, mefenamic acid is rapidly absorbed after oral administration, has a short half-life, and it is more tolerant than other NSAIDs [35]. Mefenamic acid showed relatively high peak plasma level (Cmax: 20 μg/mL or 83 μM) [45,46]. In the present work, although the exposure profile is very important for anti-parasitic activity, we found that mefenamic acid exhibited schistosomicidal activity with LC 50 values from~10 μM, which are far below the clinically achievable plasma concentrations in vivo. ...
Background:
Treatment and control of schistosomiasis, one of the most insidious and serious parasitic diseases, depend almost entirely on a single drug, praziquantel. Since the funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, 73 nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in medical and veterinary fields were evaluated for their anti-schistosomal properties.
Methods:
The efficacy of NSAIDs was first tested against adult Schistosoma mansoni ex vivo using phenotypic screening strategy, effective drugs were further tested in a murine model of schistosomiasis. The disease parameters measured were worm and egg burden, hepato- and splenomegaly.
Findings:
From 73 NSAIDs, five (mefenamic acid, tolfenamic acid, meclofenamic acid, celecoxib, and diclofenac) were identified to effectively kill schistosomes. These results were further supported by scanning electron microscopy analysis. In addition, the octanol-water partition coefficient, both for neutral and ionized species, revealed to be a critical property for the ex vivo activity profile. Compounds were then tested in vivo using both patent and a prepatent S. mansoni infection in a mouse model. The most effective NSAID was mefenamic acid, which highly reduced worm burden, egg production, and hepato- and splenomegaly.
Interpretation:
The treatment regimen used in this study is within the range for which mefenamic acid has been used in clinical practice, thus, it is demonstrated the capacity of mefenamic acid to act as a potent anti-schistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis.
... The molecular weight is 241.29. Its molecular formula is C15H15N02 [2]. ...
... An alternative hypothesis for the distinct behavioural effects observed with certain fenamates is that NSAIDs (that do not have behavioural effects) do not cross the bloodbrain barrier. At therapeutic doses mefenamic acid peak plasma concentrations have been reported to be in the range of 4|xM -40|i,M, with half bound to plasma proteins (Flower, 1974;Glazko, 1966;Court & Volans, 1984). Unfortunately at the time of writing there is no published data on the concentrations of fenamates which enter the CNS. ...
... 71 The implications of these effects are numerous, namely, pertaining to lower fraction dissolved in dogs for weakly basic drugs, and activation of pH-responsive formulations designed to release drug at specific pH ranges, thereby resulting in altered drug bioavailability. 70 Differences in absorption of such drugs between dog and human have also been demonstrated with aspirin, 72,73 chlorothiazide, 74,75 mefenamic acid, 76 and rofecoxib, 77 as well as for the peptide drug calcitonin. 78 These differences are thought to be augmented by the wide interspecies variability in dog intestinal pH, which could also confound predictions of drug release and absorption. ...
"All animals are equal, but some are more equal than others" was the illustrious quote derived from British writer George Orwell's famed work, Animal Farm. Extending beyond the remit of political allegory, however, this statement would appear to hold true for the selection of appropriate animal models to simulate human physiology in preclinical studies. There remain definite gaps in our current knowledge with respect to animal physiology, notably those of intra- and inter-species differences in gastrointestinal (GI) function, which may affect oral drug delivery and absorption. Factors such as cost and availability have often influenced the choice of animal species without clear justification for their similarity to humans, and lack of standardization in techniques employed in past studies using various animals may also have contributed to the generation of contradictory results. As it stands, attempts to identify a single animal species as appropriately representative of human physiology and which may able to adequately simulate human in vivo conditions are limited. In this review, we have compiled and critically reviewed data from numerous studies of GI anatomy and physiology of various animal species commonly used in drug delivery modeling, commenting on the appropriateness of these animals for in vivo comparison and extrapolation to humans. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.
© 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
... 13 It has been shown previously that MFA is mainly metabolized via benzylic hydroxylation to 3′-hydroxymethyl-MFA in human liver microsomes (HLM) ( Figure 1). 14,15 Inhibition studies showed that cytochrome P450 2C9 (CYP2C9) is the major enzyme involved. 3′-Hydroxymethyl-MFA is further metabolized to form the 3′-carboxy-MFA. ...
Mefenamic acid (MFA) has been associated with rare but severe cases of hepatotoxicity, nephrotoxicity, gastrointestinal toxicity and hypersensitivity reactions which are believed to result from the formation of reactive metabolites. Although formation of protein-reactive acylating metabolites by phase 2 metabolism has been well-studied and proposed as cause of these toxic side effects, the oxidative bioactivation of MFA has not yet been competely characterized. In the present study, the oxidative bioactivation of MFA was studied using human liver microsomes (HLM) and recombinant human P450 enzymes. In addition to the major metabolite 3'-OH-methyl-MFA, resulting from the benzylic hydroxylation by CYP2C9, 4'-hydroxy-MFA and 5-hydroxy-MFA were identified as metabolites resulting from oxidative metabolism of both aromatic rings of MFA. In the presence of GSH, three GSH conjugates were formed which appeared to result from GSH-conjugation of the two quinoneimines formed by further oxidation of 4'-hydroxy-MFA and 5-hydroxy-MFA. The major GSH-conjugate was identified as 4'-OH-5'glutathionyl-MFA and was formed at the highest activity by CYP1A2 and to a lesser extent by CYP2C9 and CYP3A4. Two minor GSH-conjugates resulted from secondary oxidation of 5-hydroxy-MFA and were formed at the highest activity by CYP1A2 and to a lesser extent by CYP3A4. Additionally, the ability of seven human glutathione S-transferases (hGSTs) to catalyze the GSH conjugation of the quinoneimines formed by P450s was also investigated. The highest increase of total GSH-conjugation was observed with hGSTP1-1, followed by hepatic hGSTs hGSTA2-2 and hGSTM1-1. The results of this study show that next to phase 2 metabolites, reactive quinoneimines formed by oxidative bioactivation might also contribute to the idiosyncratic toxicity of MFA.
... The present results have clinic relevance as well as significance for basic science. A low dose of oral flufenamic acid (200 mg), blood levels of the drug are in the 20-30 μM range (Glazko, 1967), which is quite close to those of IC 50 s determined in this study (Fig. 2). Moreover, an activation of outward rectifier K + current and hyperpolarization by 250 μM FFA on the circular smooth muscle of human jejunum had been related to the dosedependent FFA's common G-I side effects including diarrhea, nausea, vomiting, abdominal pain, and constipation (Farrugia et al., 1993). ...
We determined the actions of the fenamates, flufenamic acid (FFA) and niflumic acid (NFA), on gap junction-mediated intercellular coupling between vascular smooth muscle cells (VSMC) in situ of acutely isolated arteriole segments from the three vascular beds: the spiral modiolar artery (SMA), anterior inferior cerebellar artery (AICA) and mesenteric artery (MA), and on non-junctional membrane channels in dispersed VSMCs. Conventional whole-cell recording methods were used. FFA reversibly suppressed the input conductance (G(input)) or increased the input resistance (R(input)) in a concentration dependent manner, with slightly different IC(50s) for the SMA, AICA and MA segments (26, 33 and 56μM respectively, P>0.05). Complete electrical isolation of the recorded VSMC was normally reached at ≥300μM. NFA had a similar effect on gap junction among VSMCs with an IC(50) of 40, 48 and 62μM in SMA, AICA and MA segments, respectively. In dispersed VSMCs, FFA and NFA increased outward rectifier K(+)-current mediated by the big conductance calcium-activated potassium channel (BK(Ca)) in a concentration-dependent manner, with a similar EC(50) of ∼300μM for both FFA and NFA in the three vessels. Iberiotoxin, a selective blocker of the BK(Ca), suppressed the enhancement of the BK(Ca) by FFA and NFA. The K(V) blocker 4-AP had no effect on the fenamates-induced K(+)-current enhancement. We conclude that FFA and NFA blocked the vascular gap junction mediated electrical couplings uniformly in arterioles of the three vascular beds, and complete electrical isolation of the recorded VSMC is obtained at ≧300μM; FFA and NFA also activate BK(Ca) channels in the arteriolar smooth muscle cells in addition to their known inhibitory effects on chloride channels.
... MFA is known to be metabolized in humans by cytochrome P450 on the 3-methyl group forming 3-hydroxy-MFA (Glazko, 1966). Subsequent oxidation of the 3-hydroxy group leads to the formation of the 3-carboxy-MFA metabolite. ...
Carboxylic acid-containing nonsteroidal anti-inflammatory drugs (NSAIDs) can be metabolized to chemically reactive acyl glucuronide and/or S-acyl-CoA thioester metabolites capable of transacylating GSH. We investigated the metabolism of the NSAID mefenamic acid (MFA) to metabolites that transacylate GSH, leading to MFA-S-acyl-GSH thioester (MFA-SG) formation in incubations with rat and human hepatocytes and in vivo in rat bile. Thus, incubation of MFA (1-500 μM) with rat hepatocytes led to the detection of MFA-1-β-O-acyl glucuronide (MFA-1-β-O-G), MFA-S-acyl-CoA (MFA-SCoA), and MFA-SG by liquid chromatography-tandem mass spectrometric analysis. The C(max) of MFA-SG (330 nM; 10-min incubation with 100 μM MFA) was 120- to 1400-fold higher than the C(max) of drug S-acyl-GSH adducts detected from studies with other carboxylic acid drugs to date. MFA-SG was also detected in incubations with human hepatocytes, but at much lower concentrations. Inhibition of MFA acyl glucuronidation in rat hepatocytes had no effect on MFA-SG formation, whereas a 58 ± 1.7% inhibition of MFA-SCoA formation led to a corresponding 66 ± 3.5% inhibition of MFA-SG production. Reactivity comparisons with GSH in buffer showed MFA-SCoA to be 80-fold more reactive than MFA-1-β-O-G forming MFA-SG. MFA-SG was detected in MFA-dosed (100 mg/kg) rat bile, where 17.4 μg was excreted after administration. In summary, MFA exhibited bioactivation in rat and human hepatocytes and in vivo in rat, leading to reactive acylating derivatives that transacylate GSH. The formation of MFA-SG in hepatocytes was shown not to be mediated by reaction with MFA-1-β-O-G, and not solely by MFA-SCoA, but perhaps also by intermediary MFA-acyl-adenylate formation, which is currently under investigation.
... However, as with rabbit uterus in vivo and rat uterus in vitro (Levy & Lindner, 1971;Vane & Williams, 1973), meclofenamate had no significant effect on PGF2c,-induced contractions. Instead, the three fenamates tested (mefenamate, flufenamate and meclofenamate), in concentrations probably below therapeutically maximal plasma levels (Glazko, 1967), selectively blocked myometrial contractions to the PGH2 analogue U-46619. ...
1 The prostaglandin endoperoxide analogue U-46619 potently contracted human isolated myometrium, suggesting that prostaglandin H2 (PGH2) may be a major stimulant of myometrial contractions. 2 Sodium mefenamate, flufenamate or meclofenamate 2 microgram/ml greatly reduced contractions of the myometrium induced by the PGH2 analogue. 3 Flufenamate, but not the other two drugs, also significantly inhibited contractions to acetylcholine. 4 Sodium meclofenamate 2 microgram/ml did not consistently antagonize contractions to PGF2alpha. 5 The relief of dysmenorrhoea by fenamates may be explained both by inhibition of PG synthesis, and by antagonism of contractions to PGH2 produced by incompletely blocked PG synthesis.
... It has been reported that convulsions can occur in 10-20% of patients who take this drug, particularly in those who ingest large amounts or who have high plasma concentrations of the agent (Balali-Mood et al., 1981 ). The manufacturers of the compound recommend the use of activated charcoal to prevent the absorption after overdose but these recommendations are based solely on data in the rat (Glazko, 1966). We therefore felt it important to obtain the relevant information concerning the effect of charcoal on the absorption of this agent in man. ...
Mefenamic acid 500 mg orally was administered to nine healthy volunteers on four occasions 7 days apart. On two occasions allocated at random, activated charcoal (2.5 g of medicoal) was administered 1 h after the drug. Hyoscine butylbromide (20 mg intramuscularly) was given immediately after mefenamic acid on one of these occasions, and on one occasion after mefenamic acid without charcoal. Hyoscine significantly delayed the time to maximum mefenamic acid concentrations but did not affect the area under the plasma concentration-time curve. Charcoal reduced the area under the plasma concentration curve by 36% and charcoal and hyoscine reduced the area under the plasma concentration curve by 42% from their respective control values. We conclude that early charcoal administration in a ratio of 5 g to 1 g of drug effectively reduces the area under the plasma concentration-time curve after oral mefenamic acid administration. Early charcoal administration may be of value therefore in reducing the toxicity of mefenamic acid after deliberate or accidental overdosage.
... 71 The implications of these effects are numerous, namely, pertaining to lower fraction dissolved in dogs for weakly basic drugs, and activation of pH-responsive formulations designed to release drug at specific pH ranges, thereby resulting in altered drug bioavailability. 70 Differences in absorption of such drugs between dog and human have also been demonstrated with aspirin, 72,73 chlorothiazide, 74,75 mefenamic acid, 76 and rofecoxib, 77 as well as for the peptide drug calcitonin. 78 These differences are thought to be augmented by the wide interspecies variability in dog intestinal pH, which could also confound predictions of drug release and absorption. ...
To use rodent models effectively in in-vivo investigations on oral drug and vaccine delivery, the conditions in the gastrointestinal tract must be understood. Some fundamental information is currently unavailable or incomplete. We have investigated the pH, water content and lymphoid tissue distribution along the gastrointestinal tract, as well as the stomach volume, as these were critical to our investigations on pH-responsive drug delivery and colonic vaccination. The observed values were compared with those in man as an indication of the validity of the rodent model. The mouse stomach pH was 3.0 (fed) and 4.0 (fasted), and the corresponding values in the rat were 3.2 (fed) and 3.9 (fasted). The mean intestinal pH was lower than that in man (<pH 5.2 in the mouse; <pH 6.6 in the rat). This brings into question the use of rodents in investigations on enteric-coated drug carriers targeted to the large intestine/distal gut. The water content in the gastrointestinal tract in the fed and fasted mouse was 0.98+/-0.4 and 0.81+/-1.3 mL, respectively, and in the fed and fasted rat was 7.8+/-1.5 and 3.2+/-1.8 mL. When normalized for body weight, there was more water per kg body weight in the gastrointestinal tracts of the mouse and rat, than in man. The stomach capacity was found to be approximately 0.4 and 3.4 mL for mice and rats, respectively. The low fluid volume and stomach capacity have implications for the testing of solid dosage forms in these animal models. Substantial amounts of lymphoid tissue analogous to small intestinal Peyer's patches were measured in the rat and mouse colon, showing the feasibility of colonic vaccination, a route which might prove to have different applications to the more commonly studied oral vaccines. The existence of lymphoid tissue in the mouse and rat caecum has also been reported.
Clinical use of mefenamic acid has generally declined in an era where other NSAID use has flourished. While having modes of action and general toxicities similar to other NSAIDs, mefenamic acid, as a member of the fenamates, nevertheless possesses some unique in vitro effects that have the potential to distinguish this agent from others. Use of this drug remains relevant for pain syndromes and some gynecological disorders, albeit with considerable competition from other NSAIDs. New basic science has considerably improved the understanding of the biochemistry of mefenamic acid. As well as maintaining its use in traditional settings, there is a tremendous potential for expanding the application of mefenamic acid to niche roles.
Flufenamic acid, a fenamate, has been shown to alter markedly the membrane potential of small intestinal smooth muscle and increase intracellular calcium in single cells.
To determine the effects of flufenamic acid on myoelectrical motor activity and gastrointestinal transit in the intact animal.
Myoelectrical motor activity was recorded via seromuscular platinum electrodes sutured at regular intervals in the stomach and throughout the small intestine. Fasted and fed gastrointestinal transit was assessed using technetium-99m (99mTc) as the radioactive marker linked to 1 mm amberlite pellets or added to the meal.
Flufenamic acid (600 mg, intravenously) induced intense spike activity in the small intestine. The mean duration of irregular spike activity was 250 (7) minutes. Spike activity was more pronounced in the lower small intestine. Flufenamic acid also accelerated initial gastric emptying and markedly shortened transit time in the small intestine. In the fasted state the 50% transit time in the small intestine was 54 (8) minutes with infusion of flufenamic acid compared with 105 (10) minutes in the control group; in the fed state 99mTc first reached the colon at 220 (10) minutes compared with 270 (12) minutes in the control group.
Flufenamic acid had marked effects on both myoelectrical motor complex activity and small intestinal transit in the dog. The observed effects suggest that flufenamic acid may be of potential use as a prokinetic agent.
A simple, rapid and sensitive reversed-phase gradient High-Performance Liquid Chromatographic (HPLC) method is proposed for the determination of anthranilic acid derivatives in anti-inflammatory drugs and biological fluids.HPLC analyses are performed with a Lichrosorb-RP 18, 10 μm, 250×4 mm I. D., column employing gradient elution for the development of the chromatogram. The gradient system is formed with the following solutions: A = 0.065M ammonium acetate and B = methanol. The flow rate is 0.8 ml/min and the detection is achieved at 282 nm. The retention time is 4.63 min for flufenamic, 4.99 min for mefenamic and 5.46 min for tolfenamic acid. The absolute detection limits are 0.5 ng for flufenamic acid, 0.7 ng for mefenamic acid and 1.0 ng for tolfenamic acid. The linearity is observed up to 70 ng for the flufenamic acid, 70 ng for the mefenamic acid and 80 ng for the tolfenamic acid injected. The method involves the use of solid phase extraction for sample clean-up and subsequent separation of anthranilic acid derivatives and internal standard-caffeine-from endogenous interfering compounds on a reversed-phase column.The proposed method is applied to the analysis of flufenamic, mefenamic ar. d tolfenamic acid in blood serum (40 μl), urine (200 μl), tablets, capsules, suppositories, suspensions and ointment.
The non-steroidal anti-inflammatory drugs diclofenac (DCF) and mefenamic acid (MFA) were treated with the white rot fungus Phanerochaete sordida YK-624. DCF completely disappeared and MFA decreased by about 90% after 6 days of treatment. It was also confirmed that the fungus almost completely removed the acute lethal toxicity of DCF and MFA towards the freshwater crustacean Thamnocephalus platyurus after 6 days of treatment. Mass spectrometric and (1)H nuclear magnetic resonance analyses demonstrated that two mono-hydroxylated DCFs (4'-hydroxydiclofenac and 5-hydroxydiclofenac) and one di-hydroxylated DCF (4',5-dihydroxydiclofenac) were formed via fungal transformation. The four metabolites of MFA were identified as 3'-hydroxymethylmefenamic acid (mono-hydroxylated MFA), 3'-hydroxymethyl-5-hydroxymefenamic acid (di-hydroxylated MFA), 3'-hydroxymethyl-6'-hydroxymefenamic acid (di-hydroxylated MFA) and 3'-carboxymefenamic acid. These results suggest that hydroxylation catalyzed by cytochrome P450 (CYP) in P. sordida YK-624 may be involved in the elimination and detoxification of DCF and MFA. This notion was further supported by the fact that smaller decreases in DCF and MFA were observed in cultures of P. sordida YK-624 incubated with 1-aminobenzotriazole, a known inhibitor of CYP.
Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1/SVEDelta), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.
Coadministration of methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) can cause a pharmacokinetic interaction and a subsequent increase in blood methotrexate concentrations. methotrexate and most NSAIDs are excreted into urine via organic anion transporter 3 (OAT3). The purpose of this study was to evaluate NSAIDs that compete less with methotrexate by using the renal cell line stably expressing human OAT3 (S2-hOAT3) in vitro. We also confirmed the pharmacokinetic interaction of methotrexate with NSAIDs in vivo. [(3)H]methotrexate uptake into S2-hOAT3 cells was inhibited by most NSAIDs in a concentration-dependent manner, but aspirin, salicylate, tiaramide, and acetaminophen did not inhibit uptake. Inhibition by sulindac and pranoprofen was weaker at therapeutic drug concentrations. Furthermore, methotrexate concentrations in rat serum were significantly increased in a NSAID concentration-dependent manner when concentrations of coadministered NSAIDs increased above the Ki values obtained in the in vitro study. On the other hand, drugs that were not substrates of hOAT3, such as acetaminophen, did not interact with methotrexate. The magnitude of the pharmacokinetic interaction between methotrexate and NSAIDs was significantly correlated with results of the accumulation study in vitro and was not significantly correlated with a reduction of urinary creatinine excretion. In conclusion, methotrexate and most NSAIDs are substrates of hOAT3, and those drugs compete via hOAT3 in tubular secretion, the major mechanism of the interaction between methotrexate and NSAIDs. The accumulation study using S2-hOAT3 cells might be useful for screening of potential interactions between methotrexate and new NSAIDs in vivo.
Mefenamic acid suppository 500 mg was administered by rectum to eight healthy adult volunteers followed by either activated charcoal 5 g orally at hourly intervals for 7 h or an equal volume of water on two separate occasions 7 days apart. Administration of charcoal did not significantly affect the pharmacokinetic variables of mefenamic acid. Thus the beneficial effects of charcoal in the treatment of mefenamic acid overdose are largely due to interference with absorption, rather than enhancement of elimination of the drug.
The phagocytosis of killed Staphylococcus epidermidis by neutrophilic leukocytes was inhibited in vitro by indomethacin in a concentration of 3 × 10-4M, and by hydrocortisone, phenylbutazone, and paracetamol in a concentration of 10-3M. Phagocytosis was slightly stimulated by 10-7M phenylbutazone. Acetylsalicylic acid, mefenamic acid, and phenacetin had no effect. The bactericidal activity of leukocytes against live Staphylococcus epidermidis was reduced by 10-4M phenacetin, 5 × 10-4M mefenamic acid, and 10-3M phenylbutazone and indomethacin, whereas concentrations of 10-5M and above of paracetamol enhanced bacterial killing by leukocytes. Hydrocortisone and acetylsalicylic acid were ineffective. It is probable that concentrations of anti-inflammatory agents sufficient to affect phagocytosis and bacterial killing by neutrophils are as a rule not attained in the organism during treatment, although inhibition may occur locally, for example in inflamed tissue, as a consequence of a low pH, which potentiates the effect of acid anti-inflammatory drugs. This inhibition may be a factor in the mechanism of action of anti-inflammatory compounds.
Mefenamic acid ('Ponstan') overdosage has increased steadily in Edinburgh over the past 12 years. Of fifty-four patients studied prospectively only twenty-nine had plasma mefenamic acid concentrations above the therapeutic range at admission. Fourteen of these twenty-nine were symptom-free, but fifteen patients had muscle twitching which in eleven progressed to grand mal convulsions.
The antitumor effects of non-steroidal anti-inflammatory drugs (NSAIDs) have been documented in a variety of both clinical and experimental settings, although the mechanisms responsible remain unclear. In the present study, we show that the NSAIDs indomethacin and mefenamic acid inhibit the calf serum-stimulated production of hyaluronic acid (HA) in murine Swiss 3T3 fibroblasts, at concentrations where DNA synthesis is unaffected. HA is an extracellular matrix glycosaminoglycan associated with cell migration and tumor invasion. Our data suggest that one mechanism whereby NSAIDs inhibit tumor progression may be to inhibit the synthesis of HA by host fibroblasts, and that the eicosenoid pathway may represent an important control point in the growth-factor-mediated production of HA in fibroblasts. Thus the use of an agent which inhibits HA synthesis may be a novel approach to alter the invasive and metastatic properties of tumor cells in a non-cytotoxic fashion.
A method is described for the simultaneous analysis of 14 non-steroidal anti-inflammatory drugs (NSAIDS) in human serum using negative electrospray ionization-tandem mass spectrometry (ESI-MS/MS). After addition of internal standard and protein precipitation using acetonitrile, samples were transferred to autosampler vials for direct analysis without chromatography. Injection of an air bubble with the sample and a multiple reaction monitoring (MRM) method using argon collision-induced dissociation (CID) of analyte (M-H)- ions permitted integration of the product ion peak areas to produce reproducible quantitative data over the range of concentrations expected in serum during routine use of these drugs. The method permitted the analysis of 30 samples per hour. Two hundred fifty consecutive analyses did not adversely affect instrument sensitivity.
Mefenamic acid, a non-steroidal anti-inflammatory drug (NSAID), is used commonly to treat menorrhagia. This study investigated the glucuronidation kinetics of flufenamic, mefenamic and niflumic acid using human kidney cortical microsomes (HKCM) and recombinant UGT1A9 and UGT2B7. Using HKCM Michaelis-Menten (MM) kinetics were observed for mefenamic (K(m)(app) 23 microM) and niflumic acid (K(m)(app) 123 microM) glucuronidation, while flufenamic acid exhibited non-hyperbolic (atypical) glucuronidation kinetics. Notably, the intrinsic renal clearance of mefenamic acid (CL(int) 17+/-5.5 microL/minmg protein) was fifteen fold higher than that of niflumic acid (CL(int) 1.1+/-0.8 microL/minmg protein). These data suggest that renal glucuronidation of mefenamic acid may result in high intrarenal exposure to mefenamic acyl-glucuronide and subsequent binding to renal proteins. Diverse kinetics were observed for fenamate glucuronidation by UGT2B7 and UGT1A9. Using UGT2B7 MM kinetics were observed for flufenamic (K(m)(app) 48 microM) and niflumic acid (K(m)(app) 135 microM) glucuronidation and atypical kinetics with mefenamic acid. Similarity in K(m)(app) between HKCM and UGT2B7 suggests that UGT2B7 may be the predominant renal UGT isoform catalysing niflumic acid glucuronidation. In contrast, UGT1A9 glucuronidation kinetics were characterised by negative cooperativity with mefenamic (S(50) 449 microM, h 0.4) and niflumic acid (S(50) 7344 microM, h 0.4) while atypical kinetics were observed with flufenamic acid. Additionally, potent inhibition of the renal glucuronidation of the UGT substrate 'probe' 4-methylumbelliferone by flufenamic, mefenamic and niflumic acid was observed. These data suggest that inhibitory metabolic interactions may occur between fenamates and other substrates metabolised by UGT2B7 and UGT1A9 in human kidney.
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