AUTHOR=Yao Han , Luo Xingxian , Zhang Hong , An Haiyan , Feng Wanyu , Feng Yi 

TITLE=The Comparison of Plasma and Cerebrospinal Fluid R(−)- and S(+)-Flurbiprofen Concentration After Intravenous Injection of Flurbiprofen Axetil in Human Subjects

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.646196

DOI=10.3389/fphar.2021.646196

ISSN=1663-9812

ABSTRACT=Background: Flurbiprofen axetil is a prodrug that releases the active substance through enzymatic removal of the ester moiety. It is formulated through encapsulation in a lipid microsphere carrier, and widely used to treat perioperative pain. Here, we studied the distribution of R(−)- and S(+)-flurbiprofen in human plasma and cerebrospinal fluid (CSF) after intravenous injection of flurbiprofen axetil.
Methods: A total of 70 adult patients undergoing elective lower limb surgery under spinal anesthesia were given a single intravenous injection of 100-mg flurbiprofen axetil. The patients were randomly assigned to 10 groups for plasma and CSF sampling at 10 time points (5–50 min) after subarachnoid puncture and before actual spinal anesthesia. R(−)- and S(+)-flurbiprofen and CSF/plasma ratio were determined by liquid chromatography–tandem mass spectrometry.
Results: R(−)-flurbiprofen concentration ranged from 2.01 to 10.9 μg/mL in plasma and 1.46 to 34.4 ng/mL in CSF. S(+)-flurbiprofen concentration ranged from 1.18 to 10.8 μg/mL in plasma and from 2.53 to 47 ng/mL in CSF. In comparison to S(+)-flurbiprofen, R(−)-flurbiprofen concentration was significantly higher in plasma at all time points (p<0.05) except at 30 or 40 min, and lower in CSF at all time points (p<0.05) except at 10, 15 and 40 min. Analysis after correcting drug concentration for body mass index also revealed higher plasma and lower CSF R(−)-flurbiprofen concentration. In comparison to S(+)-flurbiprofen, AUC0–50 for R(−)-flurbiprofen was larger in plasma and smaller in CSF (p<0.05 for both), and accordingly smaller CSF/plasma AUC0–50 ratio (p<0.05). There was a positive correlation between R(−)-flurbiprofen concentration and S(+)-flurbiprofen concentration in plasma (r=0.725, p<0.001) as well as in CSF (r=0.718, p<0.001), and a negative correlation between plasma and CSF concentration of S(+)-flurbiprofen (r=-0.250, p=0.037), but not R(−)-flurbiprofen.
Conclusions: Distribution of R(−)- and S(+)-flurbiprofen in plasma and CSF differed significantly. Penetration of R(−)-flurbiprofen into the CNS was lower than S(+)-flurbiprofen.