Protein binding of indomethacin in human cerebrospinal fluid

Muller, Noëlle; Lapicque, Françoise; Monot, C.; Payan, E.; Gillet, Pierre; Bannwarth, B; Netter, Patrick

doi:10.1016/0006-2952(91)90039-8

Cited by 11 publications

(13 citation statements)

References 19 publications

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“…It may be related to the slower disappearance of drugs from the CSF as compared with their elimination from the central compartment [10,11]. Furthermore, ibuprofen enantiomers may be partly bound to proteins in the CSF, as previously reported for indomethacin [13]. Thus, the CSF concentrations may be higher than the free plasma concentrations at equilibrium [13].…”

Section: Discussionmentioning

confidence: 66%

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Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Bannwarth

Lapicque

Péhourcq

et al. 1995

Brit J Clinical Pharma

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Since both (R)‐ and (S)‐enantiomers of ibuprofen may act on the central nervous system, we investigated their plasma and cerebrospinal fluid (CSF) concentrations in 46 patients with nerve‐root compression pain requiring a lumbar puncture. Each patient received an oral dose of 800 mg rac‐ibuprofen. A single blood and CSF sample was drawn concomitantly from each patient at intervals between 30 min and 8 h after dosing. Both isomers peaked later in the CSF (3 h) than in the plasma (1.5 h). Their CSF concentrations became higher than their concurrent free plasma concentrations after 90 min. The estimated elimination half‐ lives of (R)‐ and (S)‐ibuprofen were 1.7 h and 2.5 h in plasma and 3.9 h and 7.9 h in CSF, respectively. The AUCCSF/AUCplasma ratios (0, 8 h) were 0.009 and 0.015 for the (R)‐ and (S)‐forms, respectively.

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Section: Discussionmentioning

confidence: 66%

“…Furthermore, ibuprofen enantiomers may be partly bound to proteins in the CSF, as previously reported for indomethacin [13]. Thus, the CSF concentrations may be higher than the free plasma concentrations at equilibrium [13].…”

Section: Discussionmentioning

confidence: 67%

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Bannwarth

Lapicque

Péhourcq

et al. 1995

Brit J Clinical Pharma

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“…Several other NSAIDs have been reported to reach CSF concentrations that are higher than unbound plasma concentrations 16 , 27 – 30 . One likely explanation for this accumulation of drugs into the CSF is that there is protein binding in the CSF, which has indeed been documented for indomethacin 31 . The concentration of proteins in the CSF is approximately 0.5% of that in plasma 32 , 33 .…”

Section: Discussionmentioning

confidence: 95%

“…16,[27][28][29][30] One likely explanation for this accumulation of drugs into the CSF is that there is protein binding in the CSF, which has indeed been documented for indomethacin. 31 The concentration of proteins in the CSF is approximately 0.5% of that in plasma. 32,33 It seems likely that the accumulation of naproxen into the CSF is, to some extent, a result of high lipophilicity and protein binding.…”

Section: Discussionmentioning

confidence: 99%

Plasma and Cerebrospinal Fluid Pharmacokinetics of Naproxen in Children

Välitalo

Kumpulainen

Manner

et al. 2012

The Journal of Clinical Pharma

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The aim of this study was to characterize pediatric pharmacokinetics and central nervous system exposure of naproxen after oral administration. The pharmacokinetics of naproxen was studied in 53 healthy children aged 3 months to 12 years undergoing surgery with spinal anesthesia. Children received preoperatively a single dose of 10 mg/kg oral naproxen suspension. A single cerebrospinal fluid (CSF) sample (n = 52) was collected at the induction of anesthesia, and plasma samples (n = 270) were collected before, during, and after the operation (up to 51 hours after administration). A population pharmacokinetic model was built using the NONMEM software. Naproxen concentrations in plasma were well described by a 2-compartment model. The estimated oral clearance (CL/F) was 0.62 L/h when linearly scaled by weight to 70 kg. The apparent volume of distribution at steady state (Vss/F) was 12.5 L /70 kg. The findings are consistent with previously reported pharmacokinetic parameters for children older than 5 years. Naproxen permeated into the CSF and reached CSF concentrations that were 4 times higher than unbound plasma concentrations. Based on these data, weight can be used as a basis for naproxen dosing in children older than 3 months of age.

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“…Furthermore, for drugs like NSAIDs, which are highly protein bund, a slight degree of binding in CSF cannot be ruled out [20]. In this respect, the mean binding percentage of indomethacin was 40% in human serum albumin solutions of 0.5 and 1 g/l [21]. This feature may explain, at least in part, why the CSF…”

Section: Relationship Between Logk' and Raucmentioning

confidence: 99%

Influence of Molecular Lipophilicity on the Diffusion of Arylpropionate Non-steroidal Anti-inflammatory Drugs into the Cerebrospinal Fluid

Matoga

Péhourcq

Lagrange

et al. 2011

Arzneimittelforschung

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The diffusion of seven arylpropionic acid non-steroidal anti-inflammatory drugs (NSAIDs) into the cerebrospinal fluid (CSF) has been investigated in male Wistar rats by means of quantitative structure-activity relationship (QSAR) study. After intraperitoneal administration of each drug (5 mg/kg), blood and CSF samples were collected at different times (0.5, 1, 3, and 6 h). The fraction bound to plasma proteins (fb) was determined using ultracentrifugation. The total (CT) and free (CF) plasma concentrations and the concentrations in CSF (CCSF) were measured by a reversed-phase high performance liquid chromatographic (RP-HPLC) method. The areas under the curve of the free plasma (AUCF) and CSF (AUCCSF) concentrations were calculated according to the trapezoidal rule. The overall drug transit into CSF was estimated by the ratio RAUC (AUCCSF: AUCF). The lipophilicity of the compounds was expressed as their polycratic capacity factors (log k'w) measured in a RP-HPLC system. The RAUC ranged from 0.24 to 6.58 and fb from 91.4 to 99.8%. The compounds with an intermediate lipophilicity value (3 < logk'w < 3.6) easily entered the CSF (RAUC > 1). A parabolic relationship was found between log k'w and log RAUC, emphasizing the role of molecular lipophilicity in the diffusion into CSF. Considering the fb value of each drug in regard to this non-linear relationship, it can be hypothesized that the diffusion rate of NSAIDs into the CSF depends primarily on the lipophilicity.

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Protein binding of indomethacin in human cerebrospinal fluid

Cited by 11 publications

References 19 publications

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Plasma and Cerebrospinal Fluid Pharmacokinetics of Naproxen in Children

Influence of Molecular Lipophilicity on the Diffusion of Arylpropionate Non-steroidal Anti-inflammatory Drugs into the Cerebrospinal Fluid

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