Variability of inversion of (R)‐flurbiprofen in different species

Menzel-Soglowek, S.; Geißlinger, Gerd; Beck, Winfried; Brune, Kay

doi:10.1002/jps.2600810909

Cited by 42 publications

(34 citation statements)

References 11 publications

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“…Unlike in rats [5,[10][11], kinetic interactions between the isomers of flurbiprofen do not appear to occur to a significant extent in humans as the enantioselective differences following racemate administration [2][3][4] were of the same magnitude as those found in the present study after administration of single enantiomers. In conclusion, flurbiprofen does not undergo gesic may be that it may lack the gastrointestinal toxicity associated with the (S)-enantiomer, as demonstrated in rats [1].…”

Section: Discussioncontrasting

confidence: 49%

Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers.

Geißlinger

Lötsch

Menzel

et al. 1994

Brit J Clinical Pharma

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Plasma concentrations of the enantiomers of flurbiprofen were measured following oral administration of (S)-flurbiprofen 50 mg and (R)-flurbiprofen 50 mg and 100 mg to sixteen healthy subjects. Chiral inversion did not occur to a measurable exent. Significantly higher values of AUC (55.2 ± 17.0 vs 44.6 ± 11.2 ig ml-' h) elimination half-life (5.6 ± 1.4 vs 4.0 ± 1.0 h) and mean residence time (7.5 ± 1.6 vs 5.7 ± 1.2 h) were observed after 50 mg (S)-flurbiprofen as compared with 50 mg (R)-flurbiprofen. With the exception of Cmax and AUC values pharmacokinetic data for the 50 mg and the 100 mg dose of (R)-flurbiprofen did not differ significantly. The data are of clinical relevance if (R)-flurbiprofen also has analgesic activity in humans and is to be developed as an analgesic.

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Section: Discussioncontrasting

confidence: 49%

Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers.

Geißlinger

Lötsch

Menzel

et al. 1994

Brit J Clinical Pharma

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“…20) Ketoprofen ethyl ester was also stable in PBS, but it was mainly hydrolyzed to R-ketoprofen in HaCaT keratinocyte PBS homogenates, and CDMB potently inhibited this hydrolysis process. These data show that carboxylesterase in HaCaT keratinocytes had substrate selectivity, and easily hydrolyzed R-ketoprofen ethyl ester (the concentrations of S-ketoprofen ethyl ester in HaCaT keratinocytes were constant), and thus HaCaT keratinocyte line was a better model for studying the prodrug metabolism of percutaneous absorption in vitro.…”

Section: Discussionmentioning

confidence: 94%

Stereoselective Characteristics and Mechanisms of Epidermal Carboxylesterase Metabolism Observed in HaCaT Keratinocytes

Zhu

Jin-hong

Liu

et al. 2007

Biological & Pharmaceutical Bulletin

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The advantages of transdermal drug delivery over other routes of administration have been well documented, including avoidance of variable absorption rates and first-pass hepatic metabolism with oral delivery and improved therapeutic activity.1) In the past, skin penetration studies usually focused only on the physicochemical factors affecting the transport of drugs across the skin. However, recently, many researchers have also been considering the concurrent epidermal metabolism. Various aspects of the metabolism of xenobiotics in the skin have been reviewed, 2) and it has been demonstrated that skin contains various enzymes including esterase capable of hydrolyzing different esters.3) Ester prodrugs for carboxylic acid-or hydroxyl-containing drugs are widely used for the enhancement of percutaneous absorption and have been noted to show stereoselective hydrolysis in various tissue preparations 4) ; surprisingly, the molecular mechanism of stereoselective hydrolysis in skin has been overlooked.A great deal of the current knowledge on the metabolic clearance of drugs in the skin is based on studies with homogenates of excised tissues, including excised animal skin or human skin. Inherent drawbacks of these models are the doubtful comparability of animal skin versus human skin, the restricted access to human skin, and the potentially high variability of enzyme activity of human skin samples along with the often poorly defined cellular viability of excised tissues. 5)It has been proposed that using cultured HaCaT keratinocytes as a readily available and reproducible in vitro metabolism model may circumvent some of these disadvantages.6) The transformed human HaCaT keratinocyte is a well-established cell model of dermal toxicity and metabolism studies in vitro, because it is easily cultured and has the characteristics of basal epidermal keratinocytes. 7)Carboxylesterase is a group of serine esterases found in numerous animal species and a variety of mammalian tissues. These enzymes hydrolyze many different endogenous and xenobiotic compounds and play a role in the metabolism of numerous drugs. 8) Some researchers have reported the purification and partial characterization of two distinct human carboxylesterases designated human carboxylesterase-1 (hCE-1) and human carboxylesterase-2 (hCE-2).9) These enzymes are expressed in human liver and are both members of the 60-kDalton serine esterase superfamily, but they differ substantially. Sequence homology between the two enzymes is only 48%. hCE-1 is an 180 kDalton trimer with an isoelectric point of 5.8, whereas hCE-2 is a monomer with an isoelectric point of 4.9. Substantial differences in substrate specificity also exist between the two isoforms. 10)Ketoprofen is a nonsteroidal antiinflammatory drug (NSAID) and is used through oral or suppository routes for the treatment of pain and inflammation. Given orally, gastrointestinal side effects are most frequently seen. Therefore percutaneous administration of ketoprofen has been studied to minimize gastrointestinal and o...

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“…At 2.25 h, mean plasma concentrations (± s.d.) were 6.39 ± 2.20 ,ug ml-' (S)-flurbiprofen, 6.91 ± 1.02 jg ml-' (R)-flurbiprofen and 11.52 ± 2.84 ig ml-(R)-flurbiprofen after administration of 50 mg (S)-flurbiprofen and 50 mg and 100 mg (R)-flurbiprofen, respectively.…”

Section: Plasma Concentrations Offlurbiprofenmentioning

confidence: 91%

Effects of flurbiprofen enantiomers on pain‐related chemo‐somatosensory evoked potentials in human subjects.

Lötsch

Geißlinger

Mohammadian

et al. 1995

Brit J Clinical Pharma

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1 The aim of the study was to investigate the analgesic effects of flurbiprofen enantiomers using an experimental pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjective pain ratings. 2 Healthy female volunteers (n = 16, age 23-36 years) participated in a placebocontrolled, randomised, double-blind, four-way crossover study. Single doses of (S)-flurbiprofen (50 mg), (R)-flurbiprofen (50 and 100 mg) and placebo were administered orally. Measurements were taken before and 2 h after administration of the medications. During each measurement, 32 painful stimuli of gaseous carbon dioxide (200 ms duration, interval approximately 30 s) of two concentrations (60 and 65% CO2 v/v) were applied to the right nostril. EEG was recorded from five positions and CSSERP were obtained in response to the painful C02-stimuli. Additionally, subjects rated the perceived intensity of the painful stimuli by means of a visual analogue scale (VAS). 3 The CSSERP-amplitude P2, a measure of analgesic effect, decreased after administration of both (R)-and (S)-flurbiprofen, while it increased after placebo. This was statistically significant at recording positions C4 (P < 0.01) and Fz (P < 0.05).The analgesia-related decreases in evoked potential produced by (R)-flurbiprofen were dose-dependent. Comparing similar doses of (R)-and (S)-flurbiprofen, the decrease in CSSERP-amplitudes produced by the (S)-enantiomer was somewhat more pronounced, indicating a higher analgesic potency. 4 The present data indicate that both enantiomers of flurbiprofen produce analgesic effects. Since (R)-flurbiprofen caused only little toxicity in rats as compared with the (S)-enantiomer or the racemic compound, a reduction of the quantitatively most important side effects in the gastrointestinal tract might be achieved by employing (R)-flurbiprofen in pain therapy.

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Variability of inversion of (R)‐flurbiprofen in different species

Cited by 42 publications

References 11 publications

Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers.

Stereoselective disposition of flurbiprofen in healthy subjects following administration of the single enantiomers.

Stereoselective Characteristics and Mechanisms of Epidermal Carboxylesterase Metabolism Observed in HaCaT Keratinocytes

Effects of flurbiprofen enantiomers on pain‐related chemo‐somatosensory evoked potentials in human subjects.

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