TY - JOUR
T1 - Quantitative targeted absolute proteomics of transporters and pharmacoproteomics-based reconstruction of P-glycoprotein function in mouse small intestine
AU - Akazawa, Takanori
AU - Uchida, Yasuo
AU - Tachikawa, Masanori
AU - Ohtsuki, Sumio
AU - Terasaki, Tetsuya
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/7/5
Y1 - 2016/7/5
N2 - The purpose of this study was to investigate whether a pharmacokinetic model integrating in vitro mdr1a efflux activity (which we previously reported) with in vitro/in vivo differences in protein expression level can reconstruct intestinal mdr1a function. In situ intestinal permeability-surface area product ratio between wild-type and mdr1a/1b (-/-) mice is one of the parameters used to describe intestinal mdr1a function. The reconstructed ratios of six mdr1a substrates (dexamethasone, digoxin, loperamide, quinidine, verapamil, vinblastine) and one nonsubstrate (diazepam) were consistent with the observed values reported by Adachi et al. within 2.1-fold difference. Thus, intestinal mdr1a function can be reconstructed by our pharmacoproteomic modeling approach. Furthermore, we evaluated regional differences in protein expression levels of mouse intestinal transporters. Sixteen (mdr1a, mrp4, bcrp, abcg5, abcg8, glut1, 4f2hc, sglt1, lat2, pept1, mct1, slc22a18, ostβ, villin1, Na+/K+-ATPase, γ-gtp) out of 46 target molecules were detected by employing our established quantitative targeted absolute proteomics technique. The protein expression amounts of mdr1a and bcrp increased progressively from duodenum to ileum. Sglt1, lat2, and 4f2hc were highly expressed in jejunum and ileum. Mct1 and ostβ were highly expressed in ileum. The quantitative expression profiles established here should be helpful to understand and predict intestinal transporter functions.
AB - The purpose of this study was to investigate whether a pharmacokinetic model integrating in vitro mdr1a efflux activity (which we previously reported) with in vitro/in vivo differences in protein expression level can reconstruct intestinal mdr1a function. In situ intestinal permeability-surface area product ratio between wild-type and mdr1a/1b (-/-) mice is one of the parameters used to describe intestinal mdr1a function. The reconstructed ratios of six mdr1a substrates (dexamethasone, digoxin, loperamide, quinidine, verapamil, vinblastine) and one nonsubstrate (diazepam) were consistent with the observed values reported by Adachi et al. within 2.1-fold difference. Thus, intestinal mdr1a function can be reconstructed by our pharmacoproteomic modeling approach. Furthermore, we evaluated regional differences in protein expression levels of mouse intestinal transporters. Sixteen (mdr1a, mrp4, bcrp, abcg5, abcg8, glut1, 4f2hc, sglt1, lat2, pept1, mct1, slc22a18, ostβ, villin1, Na+/K+-ATPase, γ-gtp) out of 46 target molecules were detected by employing our established quantitative targeted absolute proteomics technique. The protein expression amounts of mdr1a and bcrp increased progressively from duodenum to ileum. Sglt1, lat2, and 4f2hc were highly expressed in jejunum and ileum. Mct1 and ostβ were highly expressed in ileum. The quantitative expression profiles established here should be helpful to understand and predict intestinal transporter functions.
KW - P-glycoprotein/multidrug resistance protein 1a
KW - drug absorption
KW - pharmacoproteomics
KW - protein quantification
KW - quantitative targeted absolute proteomics
KW - small intestine
KW - transporter
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U2 - 10.1021/acs.molpharmaceut.6b00196
DO - 10.1021/acs.molpharmaceut.6b00196
M3 - Article
C2 - 27276518
AN - SCOPUS:84978985657
VL - 13
SP - 2443
EP - 2456
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 7
ER -