The diffusion of pirprofen into the cerebrospinal fluid in man

Zecca, Luigi; Broggini, Massimo; Pirola, Romano C.; Campi, Riccardo; Ferrario, P.; Bichisao, E.; Maresca, V.

doi:10.1007/bf00555512

Cited by 11 publications

(1 citation statement)

References 4 publications

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“…Both mechanisms may favour the removal of drugs from the CSF, and hence such drugs fail to reach a CSF/free plasma distribution ratio of unity [7]. Conversely, an additional facilitated diffusion may have contributed to the elevated RAUC (> 1) of the other ones, as suggested by earlier investigations on pirprofen [18] and fenbufen [19] in humans and rats, respectively. Furthermore, for drugs like NSAIDs, which are highly protein bund, a slight degree of binding in CSF cannot be ruled out [20].…”

Section: Relationship Between Logk' and Raucmentioning

confidence: 94%

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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Section: Relationship Between Logk' and Raucmentioning

confidence: 94%

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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Interaction of pirprofen enantiomers with human serum albumin

Oravcová

Mlynárik²,

Bystrický

et al. 1991

Chirality

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The interaction of pirprofen enantiomers with human serum albumin (HSA) was investigated by means of high-performance liquid chromatography (HPLC), circular dichroism (CD), and 1H NMR spectroscopy. HPLC experiments indicated that both pirprofen enantiomers were bound to one class of high-affinity binding sites (n(+) = 1.91 +/- 0.13, K(+) = (4.09 +/- 0.64) x 10(5) M-1, n(-) = 2.07 +/- 0.13, K(-) = (6.56 +/- 1.35) x 10(5) M-1) together with nonspecific binding (n'K'(+) = (1.51 +/- 0.21) x 10(4) M-1, n'K'(-) = (0.88 +/- 0.13) x 10(-4) M-1). Slight stereoselectivity in specific binding was demonstrated by the difference in product n(+)K(+) = (0.77 +/- 0.08) x 10(6) M-1 vs. n(-)K(-) = (1.30 +/- 0.21) x 10(6) M-1, i.e., the ratio n(-)K(-)/n(+)K(+) = 1.7. CD measurements showed changes in the binding sites located on the aromatic amino acid side chains (a small positive band at 315 nm and a pronounced negative extrinsic Cotton effect in the region 250-280 nm). The protein remains, however, in its predominantly alpha-helical conformation. The 1H NMR difference spectra confirmed that both pirprofen enantiomers interacted with HSA specifically, most probably with site II on the albumin molecule.

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Plasma and cerebrospinal fluid concentrations of indomethacin in humans

Bannwarth

Netter

Lapicque

et al. 1990

Eur J Clin Pharmacol

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Plasma and cerebrospinal fluid (CSF) concentrations of indomethacin have been determined in 52 patients hospitalized for nerve-root compression pain. Samples of blood and CSF were collected at the same time in each subject, 0.5 to 12 h after a single intramuscular injection of 50 mg indomethacin. Analgesic effect was assessed by the absolute and percentage variation in Huskisson's visual analogue scale between dosing and sampling. According to its high lipid solubility, indomethacin rapidly crossed the blood-brain barrier, being detected in CSF 0.5 h after administration. After attainment of equilibrium within 2 h, the CSF level exceeded the free plasma level. Since the drug was extensively bound to serum albumin (99.7 +/- 0.1%), this phenomenon may represent a slight degree of binding of indomethacin in CSF. The analgesic activity was not related to either the plasma or CSF concentration of indomethacin.

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The diffusion of pirprofen into the cerebrospinal fluid in man

Cited by 11 publications

References 4 publications

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

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

Interaction of pirprofen enantiomers with human serum albumin

Plasma and cerebrospinal fluid concentrations of indomethacin in humans

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