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=12

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=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results:</bold> R (−)-flurbiprofen concentration ranged from 2.01 to 10.9 μg/mL in plasma and 1.46–34.4 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 (<italic>p</italic> &lt; 0.05) except at 30 or 40 min, and lower in CSF at all time points (<italic>p</italic> &lt; 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, AUC<sub>0–50</sub> for R (−)-flurbiprofen was larger in plasma and smaller in CSF (<italic>p</italic> &lt; 0.05 for both), and accordingly smaller CSF/plasma AUC<sub>0–50</sub> ratio (<italic>p</italic> &lt; 0.05). There was a positive correlation between R (−)-flurbiprofen concentration and S (+)-flurbiprofen concentration in plasma (r = 0.725, <italic>p</italic> &lt; 0.001) as well as in CSF (r = 0.718, <italic>p</italic> &lt; 0.001), and a negative correlation between plasma and CSF concentration of S (+)-flurbiprofen (r = −0.250, <italic>p</italic> = 0.037), but not R (−)-flurbiprofen.</p><p><bold>Conclusion:</bold> Distribution of R (−)- and S (+)-flurbiprofen in plasma and CSF differed significantly. Penetration of R (−)-flurbiprofen into the CNS was lower than S (+)-flurbiprofen.</p>