Clinical Pharmacokinetics of Cerebrospinal Fluid

Bonati, Maurizio; Kanto, J.; Tognoni, Gianni

doi:10.2165/00003088-198207040-00003

Cited by 63 publications

(49 citation statements)

References 149 publications

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“…The AUCCSF/AUCtotal plasma ratios were 0.009 and 0.015 for the (R)-and the (S)-forms, respectively. In view of the low protein content of the CSF, drugs are usually assumed to be largely in the unbound form in this compartment [7]. Subsequently, the CSF concentrations were compared with the corresponding unbound plasma concentrations ( Figure 1).…”

Section: Resultsmentioning

confidence: 99%

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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: Resultsmentioning

confidence: 99%

“…The CSF white blood cell counts were normal. Thus, the blood-brain barrier may be considered as virtually undamaged [7].…”

Section: Methodsmentioning

confidence: 99%

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Bannwarth

Lapicque

Péhourcq

et al. 1995

Brit J Clinical Pharma

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“…CSF drug concentrations have been used as a common surrogate for unbound brain concentrations in clinical studies (Bonati et al, 1982;Cherubin et al, 1989;Garver, 1989;Reiter and Doron, 1996;Ostermann et al, 2004). Nevertheless, the reliability of using CSF drug concentration as a substitute has been challenged as the transport direction is different between the BBB and BCSFB for the two main efflux drug transporters, P-gp and BCRP (Bonati et al, 1982;Rao et al, 1999;de Lange and Danhof, 2002;Kusuhara and Sugiyama, 2004;Zhuang et al, 2006;de Lange, 2013;Kalvass et al, 2013). Furthermore, Gazzin et al (2008) reported that choroid plexus-associated P-gp content was less than 0.5% of the level in the cerebral microvessels, indicating that P-gp efflux is not important at the BCSFB.…”

Section: Introductionmentioning

confidence: 99%

Use of Cassette Dosing Approach to Examine the Effects of P-Glycoprotein on the Brain and Cerebrospinal Fluid Concentrations in Wild-Type and P-Glycoprotein Knockout Rats

Liu¹,

Cheong²,

Ding³

et al. 2014

Drug Metab Dispos

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The study objectives were 1) to test the hypothesis that the lack of P-glycoprotein (P-gp) and the inhibition of breast cancer resistance protein (Bcrp) at the blood-brain barrier after cassette dosing of potent P-gp and Bcrp inhibitors were due to low plasma concentrations of those inhibitors and 2) to examine the effects of P-gp on the unbound brain (C u,brain ) and cerebrospinal fluid (CSF) concentrations (C u,CSF ) of P-gp substrates in rats. In vitro inhibition of 11 compounds (amprenavir, citalopram, digoxin, elacridar, imatinib, Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1, 4-dioxopyrazino [19,29:1,6]pyrido [3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], loperamide, prazosin, quinidine, sulfasalazine, and verapamil) on P-gp and Bcrp was examined in P-gp-and Bcrpexpressing Madin-Darby canine kidney cells, respectively. An in vivo study was conducted in wild-type and Mdr1a(2/2) rats after subcutaneous cassette dosing of the 11 compounds at 1-3 mg/kg, and the brain, CSF, and plasma concentrations of these compounds were determined. At the maximal unbound concentrations observed in rats at 1-3 mg/kg, P-gp and Bcrp were not inhibited by a cassette of the 11 compounds. For non-P-gp/Bcrp substrates, similar C u,brain , C u,CSF , and unbound plasma concentrations (C u,plasma ) were observed in wild-type and P-gp knockout rats. For P-gp/Bcrp substrates, C u,brain £ C u,CSF £ C u,plasma in wild-type rats, but C u,brain and C u,CSF increased in the P-gp knockout rats and were within 3-fold of C u,plasma for six of the seven P-gp substrates. These results indicate that P-gp and Bcrp inhibition at the blood-brain barrier is unlikely in cassette dosing and also suggest that P-gp and Bcrp activity at the blood-CSF barrier is functionally not important in determination of the CSF concentration for their substrates.

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“…The passage of drugs into cerebrospinal fluid depends on many factors, including pKa, protein binding and the state of the blood-brain barrier [1]. Since ,-lactam antibiotics are weak organic acids, they penetrate the cerebrospinal fluid poorly under normal conditions [2].…”

Section: Introductionmentioning

confidence: 99%

The passage of cloxacillin into cerebrospinal fluid in the absence of meningitis.

Schievink

Mattie

Thomeer

et al. 1993

Brit J Clinical Pharma

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1 Eleven patients undergoing lumbar discectomy received cloxacillin by continuous i.v. infusion, starting before the operation. During the operation several blood samples and one CSF sample were taken.2 Mean rate constants describing the passive transfer of drug from plasma to CSF (kp) and the largely active transfer in the opposite direction (kcsF) were estimated. 3 In some subjects the CSF albumin quotient, defined as the ratio between the albumin concentration in CSF and in plasma times 1000, was slightly elevated (up to 23) which caused a significant increase in the value of kp. 4 The estimate of mean kp for healthy individuals was 0.065 h-1, which corresponds to a half-life of 10 h. The estimate of mean kcsF was 2.10 h-'. This predicts a steadystate CSF drug concentration which is 3% of the unbound plasma drug concentration. 5 There was a significant lag between the time courses of plasma and CSF drug concentrations, presumably reflecting the time for drug to move from the choroid plexus to the lumbar sampling site. 6 Four other patients received cloxacillin for prophylactic or therapeutic reasons by continuous i.v. infusion. In three of those patients the albumin quotient was normal or slightly elevated and the steady-state CCSF/Cu ratio was similar to the predicted normal value. 7 These findings indicate that eradicating staphylococci from CSF in cases of meningitis with a low degree of inflammation may be difficult.

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Clinical Pharmacokinetics of Cerebrospinal Fluid

Cited by 63 publications

References 149 publications

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Stereoselective disposition of ibuprofen enantiomers in human cerebrospinal fluid.

Use of Cassette Dosing Approach to Examine the Effects of P-Glycoprotein on the Brain and Cerebrospinal Fluid Concentrations in Wild-Type and P-Glycoprotein Knockout Rats

The passage of cloxacillin into cerebrospinal fluid in the absence of meningitis.

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