Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 350, Issue 3, Pages 578-588Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.114.214536
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Funding
- Japanese Society for the Promotion of Science (JSPS) [KAKENHI: 18109002, KAKENHI: 24249011, KAKENHI: 23790170, KAKENHI: 207291]
- Development of Creative Technology Seeds Supporting Program for Creating University Ventures and the Revitalization Promotion Program (A-STEP) from the Japan Science and Technology Agency (JST)
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The aim of this study was to investigate whether in vivo drug distribution in brain inmonkeys 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 (Kp, 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 Kp, 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 Kp, brain between monkeys and mice. Unbound brainto-plasma concentration ratios (Kp, uu, brain) were reconstructed as the reciprocal of the reconstructed in vivo P-gp functions, and the reconstructed Kp, uu, brain values were within a 3-fold range of in vivo values, which were estimated from observed Kp, 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 inmonkeys, which serve as a robust model of drug distribution in human brain.
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