Species Independence in Brain Tissue Binding Using Brain Homogenates

Di, Li; Umland, John P.; Chang, George; Huang, Yipeng; Lin, Zhen J; Scott, Dennis O.; Troutman, Matthew D.; Liston, Theodore E.

doi:10.1124/dmd.111.038778

Cited by 148 publications

(131 citation statements)

References 36 publications

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“…Large animal f u,p and f u,b for PF-4778574 and CE-157119 are listed in Table 4; values for risperidone and 9-hydroxyrisperidone are summarized in Table 5. For all evaluated compounds, rat and large animal f u,b values were effectively identical (i.e., Յ1.5-fold different), consistent with reported cross-species f u,b datasets (Summerfield et al, 2008;Di et al, 2011) and legitimizing the use of a multiple-species mean value for a large animal species lacking an experimentally determined f u,b .…”

Section: Resultssupporting

confidence: 59%

An Evaluation of Using Rat-Derived Single-Dose Neuropharmacokinetic Parameters to Project Accurately Large Animal Unbound Brain Drug Concentrations

et al. 2012

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ABSTRACT:Previous publications suggest that interstitial fluid compound concentrations (C ISF ) best determine quantitative neurotherapeutic pharmacology relationships, although confirming large animal C ISF remains elusive. Therefore, this work primarily evaluated using respective acute dose, rat-derived unbound brain compound concentration-to-unbound plasma compound concentration ratios (C b,u / C p,u ) to project accurately dog and nonhuman primate (nhp) C b,u , a C ISF surrogate, from measured C p,u for the highly permeable non-Pglycoprotein substrates N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-

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Section: Resultssupporting

confidence: 59%

An Evaluation of Using Rat-Derived Single-Dose Neuropharmacokinetic Parameters to Project Accurately Large Animal Unbound Brain Drug Concentrations

et al. 2012

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“…The Impact on K p,monkey /K p,mouse of f u,plasma also varied from 0.369 (quinidine) to 11.1 (indinavir), which was the largest variation among the four factors, suggesting that f u,plasma most significantly contributes to species variations in K p,brain values. Several studies using a variety of compounds have indicated that there are remarkable species differences in f u,plasma but no large differences in f u,brain (Fuse et al, 1998;Kratochwil et al, 2004;Di et al, 2011). Table 5 shows that f u,brain did not affect the species differences in K p,brain values of six compounds to as great an extent as f u,plasma .…”

Section: Ivive Of Brain Drug Distribution In Nonhuman Primatementioning

confidence: 86%

Blood-Brain Barrier Pharmacoproteomics-Based Reconstruction of the In Vivo Brain Distribution of P-Glycoprotein Substrates in Cynomolgus Monkeys

Uchida

Wakayama

Ohtsuki

et al. 2014

J Pharmacol Exp Ther

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The aim of this study was to investigate whether in vivo drug distribution in brain in monkeys can be reconstructed by integrating four factors: protein expression levels of P-glycoprotein (P-gp)/ multidrug resistance protein 1 at the blood-brain barrier (BBB), in vitro transport activity per P-gp molecule, and unbound drug fractions in plasma and brain. For five P-gp substrates (indinavir, quinidine, loperamide, paclitaxel, and verapamil) and one nonsubstrate (diazepam), in vitro P-gp transport activities were determined by measuring transcellular transport across monolayers of cynomolgus monkey P-gp-transfected LLC-PK1 and parental cells. In vivo P-gp functions at the BBB were reconstructed from in vitro P-gp transport activities and P-gp expression levels in transfected cells and cynomolgus brain microvessels. Brain-to-plasma concentration ratios (K p,brain ) were reconstructed by integrating the reconstructed in vivo P-gp functions with drug unbound fractions in plasma and brain. For all compounds, the reconstructed K p,brain values were within a 3-fold range of observed values, as determined by constant intravenous infusion in adult cynomolgus monkeys. Among four factors, plasma unbound fraction was the most sensitive factor to species differences in K p,brain between monkeys and mice. Unbound brainto-plasma concentration ratios (K p,uu,brain ) were reconstructed as the reciprocal of the reconstructed in vivo P-gp functions, and the reconstructed K p,uu,brain values were within a 3-fold range of in vivo values, which were estimated from observed K p,brain and unbound fractions. This study experimentally demonstrates that brain distributions of P-gp substrates and nonsubstrate can be reconstructed on the basis of pharmacoproteomic concept in monkeys, which serve as a robust model of drug distribution in human brain.

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“…Unlike the observed interspecies differences in plasma protein binding there appears to be tremendous interspecies similarity in the molecular binding of drugs to brain tissue (109). This was demonstrated by examining the binding of 47 diverse compounds representing a range of physico-chemical characteristics with a range of logD values ranging from −1.43 to 6.01.…”

Section: Binding To Cns Tissuesmentioning

confidence: 99%

Factors Influencing the Use and Interpretation of Animal Models in the Development of Parenteral Drug Delivery Systems

Martinez

2011

AAPS J

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Abstract. Depending upon the drug and drug delivery platform, species-specific physiological differences can lead to errors in the interspecies extrapolation of drug performance. This manuscript provides an overview of the species-specific physiological variables that can influence the performance of parenteral dosage forms such as in situ forming delivery systems, nanoparticles, microspheres, liposomes, targeted delivery systems, lipophilic solutions, and aqueous suspensions. Also discussed are those factors that can influence the partitioning of therapeutic compounds into tumors, the central nervous system and the lymphatics. Understanding interspecies differences in the movement and absorption of molecules is important to the interpretation of data generated through the use of animal models when studying parenteral drug delivery.

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Species Independence in Brain Tissue Binding Using Brain Homogenates

Cited by 148 publications

References 36 publications

An Evaluation of Using Rat-Derived Single-Dose Neuropharmacokinetic Parameters to Project Accurately Large Animal Unbound Brain Drug Concentrations

An Evaluation of Using Rat-Derived Single-Dose Neuropharmacokinetic Parameters to Project Accurately Large Animal Unbound Brain Drug Concentrations

Blood-Brain Barrier Pharmacoproteomics-Based Reconstruction of the In Vivo Brain Distribution of P-Glycoprotein Substrates in Cynomolgus Monkeys

Factors Influencing the Use and Interpretation of Animal Models in the Development of Parenteral Drug Delivery Systems

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