Pharmacokinetics, Pharmacodynamics and Drug MetabolismQuantitative Membrane Protein Expression at the Blood–Brain Barrier of Adult and Younger Cynomolgus Monkeys
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INTRODUCTION
Cynomolgus monkey has been considered as a model animal for humans because monkeys are the second nearest animal to humans in the evolutionary tree, and consequently, it has been used for the prediction of drug disposition in human brain. Substrates for P-glycoprotein (P-gp), such as verapamil and GR205171, were reported to be distributed more extensively in monkey brain than in rat brain,1 and it was suggested that there are species differences in drug permeability across the blood–brain
Reagents
All peptides listed in Supplementary Table 1 were purchased from Thermo Electron Corporation (Sedantrabe, Germany). Peptide purity (>95%) was provided by the manufacturer, using reversed-phase high-performance liquid chromatography with UV detection (RP-HPLC–UV, with a detection wavelength of 215 nm) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analyses. Other chemicals were commercial products of analytical grade.
Animals
Brains of cynomolgus monkeys,
Isolation of Brain Microvessels from Monkey Brain
The brain microvessels were isolated by means of a combination of dextran density separation and size filtration from the brain of neonate, child, and adult monkeys. As shown in Figure 1, microscopic analysis revealed that brain microvessels were predominantly present in the preparations obtained from the brain at each age. The diameter of the microvessels was 4–8 μm, and there was no obvious age-related difference in the characteristics of the microvessels.
Quantitative Protein Expression of Membrane Proteins in Brain Microvessels of Adult Monkeys
Protein expression amounts of
DISCUSSION
This is the first study to determine quantitatively the expression levels of membrane proteins in cynomolgus monkey brain microvessels, which constitute the BBB. Comparison with our previously reported results for mouse brain microvessels10 indicates that there is a pronounced species difference between monkey and mouse. BCRP expression in the monkey was higher than that in mouse, whereas MDR1 and MRP4 expression levels were lower than those in mouse (Table 5). OATP1A2/OATP-A expression in
Acknowledgements
This study was supported in part by a Grant-in-Aid for JSPS Fellows, Grant-Scientific Research (S), and a Global Center of Excellence (COE) Program grant from the Japan Society for the Promotion of Science. This study was also supported in part by the Industrial Technology Research Grant Program from New Energy and the Industrial Technology Development Organization of Japan. We are most grateful to Drs. Yasuyuki Ishii, Masato Chiba, Tomoyuki Ohe, and Kentaro Wakayama, Banyu Pharmaceutical Co.,
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