The Cerebrospinal Fluid Distribution of Postoperatively Administred Dexketoprofen and Etoricoxib and Their Effect on Pain and Inflammatory Markers in Patients Undergoing Hip Arthroplasty.

BACKGROUND AND OBJECTIVE: Based on earlier literature, etoricoxib may have a delayed analgesic effect in postoperative setting when analgesic efficacy of nonselective nonsteroidal anti-inflammatory drug dexketoprofen is rapid. This may be caused by slow penetration of etoricoxib into the central nervous system (CNS). Therefore we decided to determine the plasma and cerebrospinal fluid (CSF) pharmacokinetics and pharmacodynamics of dexketoprofen and etoricoxib in patients with hip arthroplasty. METHODS: A total of 24 patients, scheduled for an elective primary hip arthroplasty were enrolled. After surgery, 12 subjects were randomized to received a single intravenous dose of dexketoprofen, and 12 subjects were given oral etoricoxib. Paired blood and CSF samples were taken up to 24 h for measurement of drug concentrations, interleukin (IL)-6, IL-1ra and blood for interleukin 10. RESULTS: In CSF the highest measured concentration (C max) of dexketoprofen was 4.0 (median) ng/mL (minimum-maximum 1.9-13.9) and time to the highest concentration (t max) 3 h (2-5), and for etoricoxib C max 73 ng/mL (36-127) and t max 5 h (1-24), respectively. Opioid consumption during the first 24 postoperative hours was similar in the two groups. Dexketoprofen and etoricoxib had a similar effect on the postoperative inflammatory response. No significant differences considering pain relief or adverse events were found between the two groups. CONCLUSION: Dexketoprofen and etoricoxib entered the CNS readily, already at 30 min after administration dexketoprofen was detected in the CSF in most subjects and etoricoxib after 60 min. A single dose of dexketoprofen and etoricoxib provided a similar anti-inflammatory and analgesic response after major orthopaedic surgery.

Cerebrospinal fluid distribution of ketoprofen after intravenous administration in young children.

OBJECTIVE: The purpose of this study was to evaluate the cerebrospinal fluid (CSF) distribution of an NSAID, ketoprofen, in children. Ketoprofen concentrations were determined from the CSF, plasma and protein-free plasma samples. METHODS: Children (n = 21), aged 13-94 months, were given intravenous ketoprofen (1 mg/kg) prior to surgery under spinal anaesthesia. Single venous blood and CSF samples from each patient were collected simultaneously 7-67 minutes after the drug administration. Ketoprofen concentrations in the samples were determined using gas chromatography-mass spectrometry. RESULTS: Ketoprofen entered the CSF and was detectable in all samples. However, CSF delivery was limited; the ratio of ketoprofen concentration in CSF to plasma remained below 0.006 at all times. Ketoprofen was highly bound (> 98%) to plasma proteins. The free ketoprofen fraction was not in equilibrium with the CSF, and no clear peak drug concentration in the CSF was observed. CONCLUSION: This study shows that ketoprofen is able to enter the CSF of children, which enables central analgesic effects of ketoprofen. However, the slow distribution of ketoprofen into the CSF and the apparently low absolute concentrations has to be taken into account when central analgesic effects are desired.

Diffusion of ketoprofen into the cerebrospinal fluid of young children.

BACKGROUND: The objective was to examine whether or not ketoprofen enters the cerebrospinal fluid after a single oral dose of 1 mg.kg-1 syrup, and to find out what is the lowest plasma concentration that will achieve a measurable level in the cerebrospinal fluid. METHODS: We measured ketoprofen concentrations both in plasma and cerebrospinal fluid of 10 young and healthy children (aged 9-86 months) after surgery with spinal anaesthesia. Samples of cerebrospinal fluid were collected 30 min after drug administration, at the same time as venous blood samples. A validated high-performance liquid chromatography method with a lower limit of 0.02 microg x ml(-1) was used to detect ketoprofen concentrations in cerebrospinal fluid and plasma. RESULTS: Ketoprofen was detectable in the cerebrospinal fluid only in the child who had the highest plasma concentration, 7.4 microg x ml(-1), while at plasma concentrations 6.5 microg x ml(-1) or less, cerebrospinal fluid (CSF) concentrations remained unmeasurable. The detected CSF/plasma ratio was 0.008. CONCLUSIONS: These results indicate that ketoprofen at a dose of 1 mg x kg(-1) is too low to produce measurable CSF levels within 30 min of oral administration.

Influence of a polymeric formulation of ketoprofen on its diffusion into cerebrospinal fluid in rats.

Poly(D,L)lactide nanocapsules (NCs) have been proposed as an alternative carrier for many drugs. We investigated the influence of this formulation on the pharmacokinetics of ketoprofen in the plasma and cerebrospinal fluid (CSF). Male Wistar rats were given intraperitoneal dose of ketoprofen (5 mg/kg) in a suspension of NCs or in a carboxymethylcellulose (CMC) solution (reference preparation). Blood and CSF samples were collected at different times up to 24 h after dosing. The unbound fraction of ketoprofen in plasma (f(u)) was determined using ultrafiltration. The total (C(T)) and free (C(F)) concentrations of ketoprofen in plasma and the simultaneous CSF concentrations (C(CSF)) were measured by a HPLC method and the areas under the curve (AUC(T), AUC(F), AUC(CSF)) were calculated. AUC(T) of ketoprofen-loaded NCs in plasma was similar to that of the reference solution, while AUC(F) of the former (5.41 mg/l x h) was higher than that produced by the latter (4.03 mg/l x h). Accordingly, the unbound fraction (f(u)) was higher after administration of NCs than that of the solution (2.5 and 1.8%, respectively). Finally, AUC(CSF) were identical for both formulations. These findings suggest that the binding of ketoprofen to plasma proteins is not the major factor that governs its blood-to-CSF exchanges.

Diffusion of intramuscular ketoprofen into the cerebrospinal fluid.

Serum and cerebrospinal fluid (CSF) concentrations of ketoprofen have been measured in 36 patients hospitalised for sciatica. Diagnostic lumbar puncture was done 15 min to 13 h after a single 100 mg intramuscular dose of ketoprofen. Serum and CSF were sampled at the same time. Free serum concentrations were determined by equilibrium dialysis. Total and free concentrations were assayed by a highly sensitive and specific HPLC method. Ketoprofen rapidly crossed the blood-brain barrier and was detected in CSF 15 min after its administration. The rapid diffusion can be explained by the high lipid solubility of the drug. The CSF level was in equilibrium with the free serum concentration from the second to the 13th hours.