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

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 1.46-34.4 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, AUC_0-50 for R (-)-flurbiprofen was larger in plasma and smaller in CSF (p < 0.05 for both), and accordingly smaller CSF/plasma AUC_0-50 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. Conclusion: Distribution of R (-)- and S (+)-flurbiprofen in plasma and CSF differed significantly. Penetration of R (-)-flurbiprofen into the CNS was lower than S (+)-flurbiprofen.

Keywords: R(-)-flurbiprofen; S(+)-flurbiprofen; cerebrospinal fluid; flurbiprofen axetil; plasma.

SCHEME 1

Flowchart of patient enrollment and analysis.

FIGURE 1

Concentrations of (A,C) R (−)-flurbiprofen and (B,D) S (+)-flurbiprofen in plasma or cerebrospinal fluid (CSF) at 5–50 min after intravenous administration of 100-mg flurbiprofen axetil. Levels were measured in seven patients at each time point.

FIGURE 2

Ratios of cerebrospinal fluid (CSF)/plasma concentrations of (A) R (−)-flurbiprofen and (B) S (+)-flurbiprofen 5–50 min after intravenous administration of 100-mg flurbiprofen axetil. Levels were measured in seven patients at each time point.

FIGURE 3

Concentrations of R (−)- and S (+)-flurbiprofen in (A) plasma and (B) cerebrospinal fluid (CSF) at 5–50 min after intravenous injection of 100-mg flurbiprofen axetil. Levels were measured in seven patients at each time point. *p < 0.05.

FIGURE 4

BMI-corrected concentrations of R (−)- and S (+)-flurbiprofen in (A) plasma and (B) cerebrospinal fluid (CSF) at 5–50 min after intravenous injection of 100-mg flurbiprofen axetil (C) Ratios of CSF/plasma concentrations of R (−)- and S (+)-flurbiprofen 5–50 min after intravenous administration of 100-mg flurbiprofen axetil. Levels were measured in seven patients at each time point. *p < 0.05.