Simultaneous determination of flurbiprofen and its major metabolite in physiological fluids using liquid chromatography with fluorescence detection

Adams, Wade J.; Bothwell, Brian E.; Bothwell, W; Vangiessen, Garrett J.; Kaiser, David G.

doi:10.1021/ac00138a006

Cited by 16 publications

(7 citation statements)

References 9 publications

(18 reference statements)

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“…Flurbiprofen and the 4'-hydroxy-metabolite have previously been quantified in human serum or plasma, concentrations of 4'-hydroxyflurbiprofen being 10 to 20 times less than those of the parent drug, whereas 3'-hydroxy-4'-methoxyflurbiprofen has not been detected [11,19]. Similarly, we were unable to detect the 3 '-hydroxy-4'-methoxy-metabolite in plasma samples of a volunteer following administration of racemic flurbiprofen.…”

Section: Plasma Assaymentioning

confidence: 59%

“…Achiral chromatographic analysis of the metabolites of flurbiprofen in biological fluids has received relatively little attention in the literature [8,11,12]. Furthermore, the development of enantiospecific methods has been restricted due to the difficulties associated with the chromatographic separation and resolution of flurbiprofen and its metabolites, coupled with the lack of authentic standards of the individual enantiomers of the metabolites.…”

Section: Flurbiprofen (Rac-2-[2-fluoro-4-biphenyl]-mentioning

confidence: 99%

“…Previous assay methods have quantified the conjugates of flurbiprofen, and its metabolites, by using either base [11] or acid hydrolysis [12,14]. However, in addition to acyl glucuronidation, the metabolites of flurbiprofen undergo phenolic conjugation to form ether glucuronides and sulphate conjugates and the disadvantage of the above methodologies is that they do not differentiate between conjugation at the different sites.…”

Section: Urineassaymentioning

confidence: 99%

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Stereospecific analysis of flurbiprofen and its major metabolites in plasma and urine by chiral-phase liquid chromatography

2003

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Key WordsColumn liquid chromatography Enantiospecific chromatography Enantioselective disposition Flurbiprofen enantiomers and metabolites SummaryDirect chiral-phase HPLC methods have been developed for the determination of flurbiprofen and its major metabolites, namely 4'-hydroxyflurbiprofen and 3'-hydroxy-4'-methoxyflurbiprofen, in biological fluids using a derivatized amylose chiral stationary phase (CSP; ChiralpakAD). Quantification of all three analytes, both free and conjugated, in urine was carried out following liquid-liquid extraction using tandem ultraviolet (UV) and fluorescence detection. Determination of flurbiprofen and the 4'-hydroxy-metabolite in plasma utilized the same CSP but required modification in the mobile phase composition and sole use of fluorescence detection. The urine assay was linear (r> 0.998) bel',,veen 0.05-10 I~g mL 1, 0.1 -20 I~g mL 1 and 0.01 -2 I~g mL 1 for the enantiomers of flurbiprofen, 4'-hydroxyflurbiprofen and 3'-hydroxy-4'-methoxyflurbiprofen respectively. The plasma assay was linear (r > 0.997) bel',,veen 0.1 -6 I~g mL 1 and 0.01 -0.6 I~g mL 1 for the enantiomers of flurbiprofen and 4'-hydroxyflurbiprofen respectively. Both assays, typically yielded within-and bel',,veen-day imprecision and accuracy values less than 10% for the enantiomers of the different analytes. Initial volunteer studies suggest that the disposition of flurbiprofen displays modest enantioselectivity in humans.

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Section: Plasma Assaymentioning

confidence: 59%

Section: Flurbiprofen (Rac-2-[2-fluoro-4-biphenyl]-mentioning

confidence: 99%

Section: Urineassaymentioning

confidence: 99%

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Stereospecific analysis of flurbiprofen and its major metabolites in plasma and urine by chiral-phase liquid chromatography

2003

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“…Thus, BPOH is the main photoproduct of the nonsteroidal antiinflammatory drug flurbiprofen (FBP) in aqueous medium and is structurally related to the main FBP metabolite, 2-(2fluoro-4′-hydroxy-4-biphenyl)propanoic acid. 15 short-lived species detectable by fluorescence or transient absorption spectroscopy). The presence of a hydroxy substituent results in a bathochromic shift of the absorption spectrum (which extends beyond 300 nm), with possible photobiological implications.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In this work, we have selected 2-(2-hydroxybiphenyl-4-yl)propanoic acid (BPOH, Chart ) as probe, based on diverse structural and physicochemical considerations. Thus, BPOH is the main photoproduct of the nonsteroidal antiinflammatory drug flurbiprofen (FBP) in aqueous medium and is structurally related to the main FBP metabolite, 2-(2-fluoro-4′-hydroxy-4-biphenyl)propanoic acid . It contains a biphenyl nucleus as active chromophore (that should generate short-lived species detectable by fluorescence or transient absorption spectroscopy).…”

Section: Introductionmentioning

confidence: 99%

Intraprotein Formation of a Long Wavelength Absorbing Complex and Inhibition of Excited-State Deprotonation in a Chiral Hydroxybiphenyl

et al. 2012

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The two enantiomers of 2-(2-hydroxybiphenyl-4-yl)propanoic acid ((S)- and (R)-BPOH) have been selected as probes for human serum albumin (HSA). Photophysical characterization in the absence of protein led to emission maxima, singlet energies, quantum yields, and fluorescence lifetime values of 332 nm, 91 kcal mol(-1), and 0.28 and 1.8 ns for BPOH or 414 nm, 79 kcal mol(-1), and 0.31 and 3.3 ns for the corresponding phenolate BPO(-); the pK(a)* was found to be 1.17. In the presence of HSA, a light-absorbing ground-state complex (S)-BPOH@HSA was detected (maximum at ca. 300 nm) whose intensity increased with increasing protein concentration. The fluorescence spectra of (S)-BPOH in PBS, after addition of HSA, revealed a progressive diminution of the phenolate band, indicating that excited-state deprotonation is disfavored within the hydrophobic protein cavities. A similar trend was observed for (R)-BPOH, but the extent of deprotonation was significantly lower for this enantiomer. Addition of increasing amounts of the site II displacement probe (S)-ibuprofen ((S)-IBP) to BPOH@HSA led to a significant decrease of the absorption maximum at ca. 300 nm and to a recovery of the phenolate emission band at ca. 410 nm, which were again configuration dependent. The transient absorption spectrum of (S)-BPOH consisted on a broad band centered at 380 nm, attributed to the first triplet excited state. A dramatic enhancement of the triplet lifetimes within HSA was observed (19.0 μs within protein versus 1.3 μs in bulk PBS), although no stereodifferentiation was noticed in this case.

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Effect of nivasorexant (ACT‐539313), a selective orexin‐1‐receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects

Berger,

Kaufmann,

Berse

et al. 2023

Pharmacology Res & Perspec

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Nivasorexant, a selective orexin‐1‐receptor antagonist, has recently been assessed in the treatment of humans with binge‐eating disorder. Herein, the inhibitory potential of nivasorexant on cytochromes P450 (CYPs) 2C9, 2C19, and 3A4 was evaluated. Human liver microsomes/recombinant CYP enzymes were evaluated in vitro. In vivo, a single‐center, open‐label, fixed‐sequence study was performed in healthy adults to explore the effect of 100 mg nivasorexant administered twice daily (b.i.d.) on the pharmacokinetics (PK) of flurbiprofen (50 mg, CYP2C9), omeprazole (20 mg, CYP2C19), midazolam (2 mg, CYP3A4) making use of a cocktail approach. Plasma PK sampling was performed over 24 h on Day 1 (Cocktail alone), 8 (Cocktail + nivasorexant), and 15 (Cocktail + nivasorexant at steady state). Genotyping of subjects' CYPs was performed while safety and tolerability were also assessed. In vitro, nivasorexant inhibited CYP2C9, 2C19, and 3A4 in competitive inhibition assays with IC50 values of 8.6, 1.6, and 19–44 μM, respectively, while showing a significant time‐dependent CYP2C19 inhibition. In 22 subjects, exposure to flurbiprofen, omeprazole, and midazolam was generally higher during concomitant single‐ (i.e., area under the plasma concentration–time curve [AUC] ratio increased by 1.04‐, 2.05‐, and 1.56‐fold, respectively) and repeated‐dose (i.e., AUC ratio increased by 1.47‐, 6.84‐, and 3.71‐fold, respectively) nivasorexant administration compared with the cocktail substrates administered alone. The most frequently reported adverse event was somnolence. According to regulatory guidance, nivasorexant is classified as a moderate CYP2C19 and weak CYP3A4 inhibitor after 1 day and as a weak CYP2C9, strong CYP2C19, and moderate CYP3A4 inhibitor after 8 days of 100 mg b.i.d. administration. Clinicaltrials.gov ID: NCT05254548.

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Simultaneous determination of flurbiprofen and its major metabolite in physiological fluids using liquid chromatography with fluorescence detection

Cited by 16 publications

References 9 publications

Stereospecific analysis of flurbiprofen and its major metabolites in plasma and urine by chiral-phase liquid chromatography

Stereospecific analysis of flurbiprofen and its major metabolites in plasma and urine by chiral-phase liquid chromatography

Intraprotein Formation of a Long Wavelength Absorbing Complex and Inhibition of Excited-State Deprotonation in a Chiral Hydroxybiphenyl

Effect of nivasorexant (ACT‐539313), a selective orexin‐1‐receptor antagonist, on multiple cytochrome P450 probe substrates in vitro and in vivo using a cocktail approach in healthy subjects

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