Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 339, Issue 2, Pages 579-588Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.111.184200
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Funding
- JSPS [KAKENHI: 207291]
- Ministry of Education, Culture, Sports, Science and Technology [KAKENHI: 17081002]
- Japan Science and Technology Agency
- New Energy and the Industrial Technology Development Organization of Japan
- Proteomedix Frontiers
- [KAKENHI: 18109002]
- Grants-in-Aid for Scientific Research [23790170] Funding Source: KAKEN
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The purpose of this study was to examine whether in vivo drug distribution to the brain can be reconstructed by integrating P-glycoprotein (P-gp)/mdr1a expression levels, P-gp in vitro activity, and drug unbound fractions in mouse plasma and brain. For 11 P-gp substrates, in vitro P-gp transport activities were determined by measuring transcellular transport across monolayers of mouse P-gp-transfected LLC-PK1 (L-mdr1a) and parental cells. P-gp expression amounts were determined by quantitative targeted absolute proteomics. Unbound drug fractions in plasma and brain were obtained from the literature and by measuring brain slice uptake, respectively. Brain-to-plasma concentration ratios (K-p brain) and its ratios between wild-type and mdr1a/1b(-/-) mice (K-p brain ratio) were obtained from the literature or determined by intravenous constant infusion. Unbound brain-to-plasma concentration ratios (K-p,K-uu,K-brain) were estimated from K-p brain and unbound fractions. Based on pharmacokinetic theory, K-p brain ratios were reconstructed from in vitro P-gp transport activities and P-gp expression amounts in L-mdr1a cells and mouse brain capillaries. All reconstructed K-p brain ratios were within a 1.6-fold range of observed values. K-p brain then was reconstructed from the reconstructed K-p brain ratios and unbound fractions. K-p,K-uu,K-brain was reconstructed as the reciprocal of the reconstructed K-p brain ratios. For quinidine, loperamide, risperidone, indinavir, dexamethasone, paclitaxel, verapamil, loratadine, and diazepam, the reconstructed K-p brain and K-p,K-uu,K-brain agreed with observed and estimated in vivo values within a 3-fold range, respectively. Thus, brain distributions of P-gp substrates can be reconstructed from P-gp expression levels, in vitro activity, and drug unbound fractions.
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