Toward an improved prediction of human<b><i>in vivo</i></b>brain penetration

Summerfield, Scott; Lucas, A.; Porter, Rod A.; Jeffrey, Phil; Gunn, Roger N.; Read, K.; Stevens, Alexander J.; Metcalf, Ann; Osuna, M C; Kilford, Peter; Passchier, Jan; Ruffo, Alberto

doi:10.1080/00498250802499459

Cited by 100 publications

(65 citation statements)

References 71 publications

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“…Wan et al (2007) showed that rat and mouse brain fraction unbound had good correlation (R 2 ϭ 0.9887, n ϭ 25). Summerfield et al (2008) observed that brain fraction unbound among rat, Landrace pig, and human correlated well (R 2 Ͼ 0.9, n ϭ 21). In a review article, Read and Braggio (2010) reported that brain fraction unbound was conserved in eight species (dog, cynomolgus monkey, guinea pig, rat, man, marmoset, pig, and mouse) using a limited number of test compounds (seven compounds).…”

Section: Introductionmentioning

confidence: 87%

Species Independence in Brain Tissue Binding Using Brain Homogenates

Umland²,

Chang³

et al. 2011

Drug Metab Dispos

146

120

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Section: Introductionmentioning

confidence: 87%

Species Independence in Brain Tissue Binding Using Brain Homogenates

Umland²,

Chang³

et al. 2011

Drug Metab Dispos

146

120

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“…Quantification of a drug's plasma protein binding [and hence fraction unbound in plasma (fup)] is essential for extrapolation of preclinical efficacy data, prediction of in vivo clearance from in vitro data, and estimation of free drug concentration in tissues (Kalvass and Maurer, 2002;Summerfield et al, 2008;He et al, 2009). Interspecies differences in plasma protein binding (PPB) need to be considered for prediction of volume of distribution and clearance in humans (Benet and Hoener, 2002).…”

Section: Introductionmentioning

confidence: 99%

Control and Measurement of Plasma pH in Equilibrium Dialysis: Influence on Drug Plasma Protein Binding

Curran¹,

Claxton²,

Hutchison³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Past publications have highlighted the influence of postdialysis plasma pH on the measured fraction unbound in plasma (fup). There is disparity in the industry as to which of two main methods is more suitable for controlling postdialysis plasma pH: the use of either a stronger buffer or a CO 2 atmosphere for the incubation. In the current study, it has been found that 10% CO 2 could be too high for the buffering capacities of both 100 mM sodium phosphate (pH 7.40 decreased to pH 6.90 after a 6-h incubation) and plasma (decreased below pH 7.40 after a 6-h incubation). To provide appropriate control over the postdialysis plasma pH, for a range of species, it is proposed that a standard phosphate buffer strength (100 mM) and pH (7.40) in combination with a 5% CO 2 atmosphere be used for equilibrium dialysis. Furthermore, statistically significant differences in fup values obtained with a pH difference of less than 0.32 pH unit have been demonstrated. An acceptance range for postdialysis plasma pH in routine in vitro fup screening assays of pH 7.40 ؎ 0.10 is recommended.

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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.…”

mentioning

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

167

141

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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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Toward an improved prediction of humanin vivobrain penetration

Cited by 100 publications

References 71 publications

Species Independence in Brain Tissue Binding Using Brain Homogenates

Species Independence in Brain Tissue Binding Using Brain Homogenates

Control and Measurement of Plasma pH in Equilibrium Dialysis: Influence on Drug Plasma Protein Binding

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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