Evaluation of Cerebrospinal Fluid Concentration and Plasma Free Concentration As a Surrogate Measurement for Brain Free Concentration

Liu, Xingrong; Smith, Bill J.; Chen, Cuiping; Callegari, Ernesto; Becker, Stacey L.; Chen, Xi; Cianfrogna, Julie; Doran, Angela C.; Doran, Shawn D.; Gibbs, John P.; Hosea, Natilie; Liu, Jianhua; Nelson, Frederick; Szewc, Mark A; Deusen, Jeffrey Van

doi:10.1124/dmd.105.008201

Cited by 147 publications

(127 citation statements)

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“…The ratio of plasma caffeine to CSF caffeine is close to 1 in rats (10). Assuming the cellular conditions in humans and rats are comparable in this respect, the IC 50 for plasma will then lead to a CSF concentration of 67 mM, which is about half the in vitro value.…”

Section: Discussionmentioning

confidence: 87%

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Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

et al. 2012

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Caffeine is the neuroactive agent in coffee and tea and is a broadly consumed stimulant. It is a nonselective antagonist of the neuromodulator adenosine and, if applied in commonly consumed doses, evokes its stimulating effects through the blockade of adenosine receptors. 18 F-8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ( 18 F-CPFPX) has been established as a highly selective and affine PET ligand for the A 1 adenosine receptor (A 1 AR). The objective of the present study was to visualize and quantify the in vivo occupancy of the human cerebral A 1 AR by caffeine using 18 F-CPFPX and PET. Methods: Fifteen subjects (age range, 24-68 y) underwent a 140-min bolus-plus-constant-infusion PET experiment after at least 36 h of caffeine abstinence. Metabolite-corrected blood data were used to calculate steady-state distribution volumes (V T ) during the baseline condition of the scan between 70 and 90 min. Subsequently, subjects received a 10-min infusion of varying concentrations (0.5-4.3 mg/kg of body weight) of caffeine at 90 min. Occupancy V T of the A 1 AR was thereafter estimated using data acquired between 120 and 140 min. Occupancy levels were calculated using the Lassen plot, from which the inhibitory concentrations of 50% were derived. Plasma levels of caffeine were determined at regular intervals. One subject received an intravenous vehicle as a placebo. Results: Caffeine displaced 5%-44% of 18 F-CPFPX binding in a concentration-dependent manner. There was no change of radioligand binding after the administration of placebo. Halfmaximal displacement was achieved at a plasma caffeine concentration of 67 mM, which corresponds to 450 mg in a 70-kg subject or approximately 4.5 cups of coffee. Conclusion: Given a biologic half-life of about 5 h, caffeine might therefore occupy up to 50% of the cerebral A 1 AR when caffeinated beverages are repeatedly consumed during a day. Furthermore, the present study provides evidence that 18 F-CPFPX PET is suitable for studying the cerebral actions of caffeine, the most popular neurostimulant worldwide.

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Section: Discussionmentioning

confidence: 87%

“…The plasma-to-cerebrospinal fluid (CSF) ratio was reported to be 1 for caffeine (10) at equilibrium conditions. CSF concentrations of caffeine will therefore amount to approximately 50 mM (molar weight of caffeine, 194.19 g/mol) after intake of the aforementioned dose of caffeine, which is frequently consumed on a daily basis.…”

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confidence: 99%

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

et al. 2012

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“…The free brain concentration is estimated from the CSF concentration for moderate to high-permeability compounds. 28 The CSF levels of the 4-(6-fluoropyridin-3-yl)imidazoline derivatives 2a, 2c, 2e, and 2g are remarkably high due to their high brain levels and improved CSF-to-brain ratios. It should be noted that an excellent correlation was observed between the log D 7.4 values and CSF-to-brain ratios ( Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Discovery of Tetrasubstituted Imidazolines as Potent and Selective Neuropeptide Y Y5 Receptor Antagonists: Reduced Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity and Potent Antiobesity Effect

et al. 2009

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A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp 34 NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

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“…In this approach the unbound fraction in brain tissue is estimated by the unbound fraction in brain homogenate, which is determined using equilibrium dialysis or ultracentrifugation. Several indirect validation studies have been published, such as comparing the projected brain to plasma concentration ratios with the observed ratios, or comparing the unbound brain fraction determined by brain homogenate method with that determined by brain slice method, or by CSF method (Kalvass and Maurer, 2002;Maurer et al, 2005;Becker and Liu, 2006;Liu et al, 2006;Summerfield et al, 2006Summerfield et al, , 2008. Recently, Fridén et al (2007) showed that C ub predicted C m within 3-fold of error for 10 of 15 compounds.…”

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confidence: 99%

Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid

Liu

Natta²,

Yeo³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (C ub ), cerebral spinal fluid concentration (C CSF ), and unbound plasma concentration (C up ) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (C m ). Nine compounds-carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental-were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1-9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the C ub s were within 3-fold of their C m ; thiopental had a C m 4-fold of its C ub . The C CSF s of eight of the nine compounds were within 3-fold of their corresponding C m ; 9-hydroxyrisperidone showed a C CSF 5-fold of its C m . The C up s of five of the nine compounds were within 3-fold of their C m ; four compounds (ganciclovir, metoclopramide, quinidine, and 9-hydroxyrisperidone) had C up s 6-to 14-fold of their C m . In conclusion, the C ub and C CSF were within 3-fold of the C m for the majority of the compounds tested. The C up s were within 3-fold of C m for lipophilic non-P-glycoprotein (؊P-gp) substrates and greater than 3-fold of C m for hydrophilic or P-gp substrates. The present study indicates that the brain homogenate and cerebral spinal fluid methods may be used as surrogate methods to predict brain interstitial fluid concentrations within 3-fold of error in drug discovery and development settings.For drugs with an intended action in the central nervous system it is assumed that unbound drug in brain interstitial fluid is in direct contact or in equilibrium with the site of action (de Lange and Danhof, 2002). Therefore, in preclinical and clinical pharmacokinetic/pharmacodynamic studies, it is critical to determine the concentration in the interstitial fluid for brain-targeted compounds. Unbound plasma concentration (C up ) has been used to represent the unbound concentration in tissue (Wilkinson, 2001). Because the brain is separated from the plasma by the blood-brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB), C up may not represent the interstitial fluid concentration (Davson and Segal, 1995;Hammarlund-Udenaes et al., 2008;Liu et al., 2008).Microdialysis has been considered as a standard approach to measure interstitial fluid concentration (C m ) (Joukhadar and Müller, 2005;Chaurasia et al., 2007). Although this technique has been developed for more than 2 decades, it is primarily used for determination of neurotransmitters and not drug concentrations in the brain. The main limitations of this technique include high resource requirements, low throughput, and special surgical skills to set up the experiment. In addition, many compounds in the discovery stage are often very lipophilic, and it is difficult to apply microdialysis technique to study these compounds because of high nonspecific bindi...

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Evaluation of Cerebrospinal Fluid Concentration and Plasma Free Concentration As a Surrogate Measurement for Brain Free Concentration

Cited by 147 publications

References 25 publications

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

Discovery of Tetrasubstituted Imidazolines as Potent and Selective Neuropeptide Y Y5 Receptor Antagonists: Reduced Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity and Potent Antiobesity Effect

Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid

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Evaluation of Cerebrospinal Fluid Concentration and Plasma Free Concentration As a Surrogate Measurement for Brain Free Concentration

Cited by 147 publications

References 25 publications

Caffeine Occupancy of Human Cerebral A1 Adenosine Receptors: In Vivo Quantification with 18F-CPFPX and PET

Caffeine Occupancy of Human Cerebral A1 Adenosine Receptors: In Vivo Quantification with 18F-CPFPX and PET

Discovery of Tetrasubstituted Imidazolines as Potent and Selective Neuropeptide Y Y5 Receptor Antagonists: Reduced Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity and Potent Antiobesity Effect

Unbound Drug Concentration in Brain Homogenate and Cerebral Spinal Fluid at Steady State as a Surrogate for Unbound Concentration in Brain Interstitial Fluid

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Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET

Caffeine Occupancy of Human Cerebral A₁ Adenosine Receptors: In Vivo Quantification with ¹⁸F-CPFPX and PET