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

Patel, Bhavesh; Valentová, Jindra; Hutt, Andrew J.

doi:10.1007/bf02497471

Cited by 5 publications

(3 citation statements)

References 18 publications

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“…Full details of the analytical methodologies employed, including their development, validation and preliminary application to samples of biological origin, have been reported by Patel et al (2002Patel et al ( , 2003. Brief details of each method are presented below.…”

Section: Methodsmentioning

confidence: 99%

Disposition of flurbiprofen in man: influence of stereochemistry and age

Patel

Jackson²,

Swift³

et al. 2003

Xenobiotica

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1. The stereoselective metabolism and pharmacokinetics of the enantiomers of flurbiprofen were investigated following the oral administration of the racemic drug (100 mg) to four young and four elderly healthy volunteers (two males and two females per group). 2. The stereochemical composition of the drug and the 4'-hydroxy- metabolite in serum and the drug, 4'-hydroxy- and 3'-hydroxy-4'-methoxy- metabolites, both free and conjugated, in urine were determined by a direct chromatographic method of enantiomeric analysis. 3. Modest enantioselectivity in clearance (CL S/R: young, 0.86; elderly, 0.88) was largely responsible for the apparent elimination half-life of (S)-flurbiprofen being significantly greater (p<0.01) than that of the R-enantiomer in both age groups (young, S: 5.2 +/- 0.7 versus R: 4.5 +/- 0.6 h; elderly, S: 9.6 +/- 1.2 versus R: 7.1 +/- 1.0 h). The serum concentrations of 4'-hydroxyflurbiprofen were five- to 20-fold lower than those of the corresponding drug enantiomers, stereoselective disposition being evident in the significantly greater (p<0.05) apparent half-lives of the S- compared with the R-enantiomer in both groups (young, S: 10.6 +/- 2.4 versus R: 6.7 +/- 1.1 h; elderly, S: 13.7 +/- 1.7 versus R: 10.2 +/- 1.2 h). 4. Some 60 and 72% of the dose was excreted in 24-h urine in elderly and young volunteers, respectively, a significantly greater (p<0.05) proportion of which was of the R-configuration in both age groups (S/R: young, 0.87; elderly, 0.81). The major urinary excretion products were flurbiprofen and 4'-hydroxyflurbiprofen, and their acyl-conjugates in both groups. 5. Age-associated differences in the pharmacokinetics of flurbiprofen occurred in a non-stereoselective manner and were primarily as a consequence of a significant approximately 40% decrease (p<0.01) in clearance of both enantiomers in the elderly due to reduced metabolic activity. Consequently, the elderly had greater exposure to both enantiomers, as reflected by the AUCs(0-inf) being significantly higher (p<0.05), by 60%, in this age group compared with the young. 6. The findings suggest that age-related alterations in the disposition of flurbiprofen could have significant implications for the use of the drug in the elderly.

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Section: Methodsmentioning

confidence: 99%

Disposition of flurbiprofen in man: influence of stereochemistry and age

Patel

Jackson²,

Swift³

et al. 2003

Xenobiotica

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“…Examples of flurbiprofen enantiomers separation, using a Chiralpak AD stationary phase as chiral selector, can be found in the literature. Patel et al used a hexane/isopropyl alcohol/trifluoracetic acid (90/10/0.05%, v/v) mobile phase composition and obtained a selectivity value of 1.7 [13,14]. A similar mobile phase composition (95/5/1) was used by Booth and collaborators, using the same stationary phase [15].…”

Section: Introductionmentioning

confidence: 94%

Optimization of the mobile phase composition for preparative chiral separation of flurbiprofen enantiomers

Ribeiro

Graça

Pais

et al. 2009

Separation and Purification Technology

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“…3). We have previously reported on various chromatographic approaches for the separation and resolution of the drug and its two major urinary metabolites [141] and developed methodology for the determination of the stereochemical composition of the drug and its major plasma and urinary metabolites following administration of the racemate to man [142,143]. In order to develop an alternative rapid approach, and exploit the reported advantages of CE, to this analytical problem we have recently examined the resolution of flurbiprofen and Reproducibility of the electrophoretic analysis of flurbiprofen and its metabolites in urine.…”

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confidence: 99%

Enantiomeric resolution of 2‐arylpropionic acid nonsteroidal anti‐inflammatory drugs by capillary electrophoresis: Methods and applications

Patel¹,

Hanna-Brown²,

Hadley³

et al. 2004

Electrophoresis

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The 2-arylpropionic acids (2-APAs) are an important group of nonsteroidal anti-inflammatory drugs. These agents, the majority of which are available as racemates, exhibit stereoselectivity in both their action and disposition. Developments in stereoselective separation science methodology, mainly chromatographic, have facilitated an evaluation of the pharmacological properties of the individual enantiomers of these drugs and contributed to our understanding of both their mode(s) of action and disposition. While a number of electrophoretic techniques, including capillary electrophoresis, capillary electrochromatography and isotachophoresis, have been applied to the stereoselective resolution and stereospecific analysis of these agents using a variety of chiral selectors, e.g., cyclodextrins, oligosaccharides, macrocyclic antibiotics, and proteins, the number of published applications in pharmaceutical and biomedical analysis remains relatively limited. However, the utility of electrophoretic techniques for stereospecific analysis may be illustrated using the 2-APAs as typical examples of chiral acidic pharmaceuticals. Applications include: determination of enantiomeric composition following biosynthetic stereoselective hydrolysis; examination of both achiral and chiral impurity profiles in bulk drugs and formulated products; determination of enantiomeric impurities in both bulk drugs and formulated products; examination of configurational stability following stress testing of formulated products; determination of enantiomeric composition and metabolite profile in biological fluids following administration of the racemates and individual enantiomers. It may be anticipated that future exploitation of electrophoretic approaches to the stereospecific analysis of these agents will result in further contributions to our understanding of their stereoselective biological properties and therapeutic use.

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

Cited by 5 publications

References 18 publications

Disposition of flurbiprofen in man: influence of stereochemistry and age

Disposition of flurbiprofen in man: influence of stereochemistry and age

Optimization of the mobile phase composition for preparative chiral separation of flurbiprofen enantiomers

Enantiomeric resolution of 2‐arylpropionic acid nonsteroidal anti‐inflammatory drugs by capillary electrophoresis: Methods and applications

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