Inhibition of the Rat Hepatic Microsomal Flurbiprofen Acyl Glucuronidation by Bile Acids

Mano, Nariyasu; Goto, Takaaki; Nikaido, Ayako; Narui, Takashi; Goto, Junichi

doi:10.1002/jps.10475

Cited by 6 publications

(3 citation statements)

References 24 publications

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“…It should be noted that the glucuronidation biotransformation of the ( S )-PZQ phase I metabolites was greater than for the ( R )-PZQ phase I metabolites, which might explain why ( R )-PZQ exhibited enhanced therapeutic activity in vivo . Some studies have reported the side-effects produced by active glucuronides [33–36], such as the withdrawal of benoxaprofen from world markets [37], which mainly resulted from toxicity related to hepatic metabolism via glucuronidation and the correlation between glucuronide covalent binding with proteins to the risk of idiosyncratic drug toxicity (IDT) [38]. Although the glucuronides of PZQ detected are not acyl glucuronides, the possibility of active glucuronides being generated should also be considered in the future studies of PZQ toxicity.…”

Section: Discussionmentioning

confidence: 99%

Metabolic profiling of praziquantel enantiomers

Wang

Fang

Zheng

et al. 2014

Biochemical Pharmacology

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Praziquantel (PZQ), prescribed as a racemic mixture, is the most readily available drug to treat schistosomiasis. In the present study, ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) based metabolomics was employed to decipher the metabolic pathways and enantioselective metabolic differences of PZQ. Many phase I and four new phase II metabolites were found in urine and feces samples of mice 24h after dosing indicating that the major metabolic reaction encompassed oxidation, dehydrogenation, and glucuronidation. Differences in the formation of all these metabolites were observed between (R)-PZQ and (S)-PZQ. In an in vitro phase I incubation system, the major involvement of CYP3A, CYP2C9, and CYP2C19 in the metabolism of PZQ, and CYP3A, CYP2C9, and CYP2C19 exhibited different catalytic activity towards the PZQ enantiomers. Apparent Km and Vmax differences were observed in the catalytic formation of three mono-oxidized metabolites by CYP2C9 and CYP3A4 further supporting the metabolic differences for PZQ enantiomers. Molecular docking showed that chirality resulted in differences in location and conformation, which likely accounts for the metabolic differences. In conclusion, in silico, in vitro, and in vivo methods revealed the enantioselective metabolic profile of praziquantel.

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Section: Discussionmentioning

confidence: 99%

Metabolic profiling of praziquantel enantiomers

Wang

Fang

Zheng

et al. 2014

Biochemical Pharmacology

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“…58 As noted above, bile acids are readily glycosidated in vivo, and both they and their conjugates inhibit the glucuronidation of flurbiprofen 20 by hepatic microsomes. 59 It has been suggested that this inhibitory activity might limit the in vivo formation of AGs from drugs and consequently the expression of their hepatotoxicity.…”

Section: Interaction Of Acyl Glucuronides With Biomoleculesmentioning

confidence: 99%

Acyl Glucuronides: Biological Activity, Chemical Reactivity, and Chemical Synthesis

et al. 2006

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which after mutarotation at C(1) may transfer the acyl group back to the 1R-OH. This has been conclusively demonstrated by NMR spectroscopy. 14,30 Other rearranged forms of AGs are also known. When the Mitsunobu synthesis 32 (see Synthesis) is used, lactones of type 5 are byproducts, sometimes in appreciable yields. The mechanism of formation is not clear but presumably involves cyclization of the first-formed intermediate ester. If there were an in vivo route to such lactones via free carboxyl acyl glucuronides, they would doubtless be potent acylating agents, transferring in this case the sugar along with the acyl residue.Concerning 1β-AGs of benzoic acids, the chemical stability/ reactivity may be predicted with some confidence by a Hammett correlation, 33 as discussed in detail later (NMR section). Some preliminary studies have been carried out on the computational chemistry modeling of the relative stabilities of the isomers of the AGs of 2-, 3-, and 4-trifluoromethylbenzoic acids. 34 For nonarylcarboxylic acids, the structure-reactivity is more complex. Certainly branching at the R-carbon is a factor leading to increased stability; thus the AGs of gemfibrozil 6, 35 clofibric acid 7 36 and valproic acid 8, 37 all doubly R-substituted, display long half-lives (from about 6-70 h in pH 7.4 buffer 37 ).AGs derived from NSAIDs such as naproxen 9 and ibuprofen 10 generally have half-lives from 1 to 4 h under the same conditions. 38 In such compounds, an additional complication is the different rates of rearrangement of the (R)-and (S)-AG diastereoisomers. In the case of 2-phenylpropanoic acid itself 11, 38 this rate was found to be about twice as fast for the (2R)as for the (2S)-AG epimer, and this ratio is typical of the 2-aryl propanoate class. Scheme 2. Possible Fates of AGs Scheme 3. Reactivity of Acyl Glucuronides a a Clearly the rearrangement (pathway 2) requires migration of the acyl group at least as far as O(3).

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“…For instance, 8 0 -hydroxyefavirenz 17 as well 4 0 -hydroxyflurbiprofen are known to be glucuronidated. 18,19 To the best of our knowledge, it has so far not been investigated whether caffeine, paraxanthine, omeprazole, 5 0 -hydroxyomeprazole, metoprolol and α-hydroxymetoprolol are subject to conjugation with glucuronic acid. Consequently, the influence of deglucuronidation on the serum concentrations of the substrates used in the Basel phenotyping cocktail has so far not been examined systematically.…”

Section: Introductionmentioning

confidence: 99%

Effect of deglucuronidation on the results of the Basel phenotyping cocktail

Bachmann

Duthaler

Krähenbühl

2021

Brit J Clinical Pharma

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We investigated the effect of deglucuronidation on the plasma concentration of the constituents of the Basel phenotyping cocktail and on the interpretation of the phenotyping results under basal conditions and after cytochrome P450 (CYP) induction with metamizole. The cocktail containing caffeine (CYP1A2), efavirenz (CYP2B6), flurbiprofen (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6) and midazolam (CYP3A4) was administered to 12 healthy subjects before (basal) and after treatment with metamizole for 1 week. In the basal state, deglucuronidation caused an increase in the plasma concentrations and area under the curve (AUC) of metoprolol, 8′‐hydroxyefavirenz, 4′‐hydroxyflurbiprofen and 1′‐hydroxymidazolam. This effect could be visualized in Bland–Altman plots, where the values for 8′‐hydroxyefavirenz, 4′‐hydroxyflurbiprofen and 1′‐hydroxymidazolam were mostly above the +20% threshold. As a result, the metabolic ratio (MR), calculated as AUCparent drug/AUCmetabolite, decreased with deglucuronidation for CYP2B6, CYP2C9 and CYP3A4 and increased for CYP2D6. Treatment with metamizole, a constitutive androstane receptor‐dependent inducer of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, accentuated the effect of deglucuronidation on AUC and MR. The correlation of MRs calculated as the plasma concentration ratio parent drug/metabolite with the MR calculated as the AUC ratio showed that 1 sample obtained between 2 and 6 hours after cocktail ingestion and analysed with and without deglucuronidation is sufficient to obtain reliable phenotyping results. Importantly, CYP2C9 and 3A4 induction would have been missed without deglucuronidation of the plasma samples. In conclusion, deglucuronidation of the plasma samples improves the stability of the phenotyping results of the Basel phenotyping cocktail and is necessary to reliably detect CYP induction.

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Inhibition of the Rat Hepatic Microsomal Flurbiprofen Acyl Glucuronidation by Bile Acids

Cited by 6 publications

References 24 publications

Metabolic profiling of praziquantel enantiomers

Metabolic profiling of praziquantel enantiomers

Acyl Glucuronides: Biological Activity, Chemical Reactivity, and Chemical Synthesis

Effect of deglucuronidation on the results of the Basel phenotyping cocktail

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