Blood-brain barrier pharmacoproteomics-based reconstruction of the in vivo brain distribution of P-glycoprotein substrates in cynomolgus monkeys

Yasuo Uchida, Kentaro Wakayama, Sumio Ohtsuki, Masato Chiba, Tomoyuki Ohe, Yasuyuki Ishii, Tetsuya Terasaki

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31 Citations (Scopus)

Abstract

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 mono-layers 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 K p,brain between monkeys and mice. Unbound brain-to-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 in monkeys, which serve as a robust model of drug distribution in human brain.

Original languageEnglish
Pages (from-to)578-588
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume350
Issue number3
DOIs
Publication statusPublished - 2014 Sep

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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