PMID- 28479352
OWN - NLM
STAT- MEDLINE
DCOM- 20180507
LR  - 20181202
IS  - 1520-6017 (Electronic)
IS  - 0022-3549 (Linking)
VI  - 106
IP  - 9
DP  - 2017 Sep
TI  - Determinants of Intestinal Availability for P-glycoprotein Substrate Drugs 
      Estimated by Extensive Simulation With Mathematical Absorption Models.
PG  - 2771-2779
LID - S0022-3549(17)30336-2 [pii]
LID - 10.1016/j.xphs.2017.04.065 [doi]
AB  - In this study, intestinal drug-drug interactions (DDIs) for substrate drugs of 
      P-glycoprotein were simulated extensively using the extended Q(Gut) model and 
      translocation model to explore the determinants of DDI. The results of analyses 
      using both models suggested that permeability and active efflux clearance were 
      the major factors that influenced the fraction absorbed (F(A)). The results of 
      simulation for 100 virtual drugs in which parameters were generated considering 
      the actual values of commercially available drugs suggested that the ratio of the 
      pH-corrected passive permeability to the intrinsic efflux clearance 
      (P(u)/CL(eff)) relative to that of digoxin would be a useful and quantitative 
      index of P-glycoprotein (P-gp)-mediated DDI risk at lower doses. At higher doses, 
      such as 100 mg, the risk of P-gp-mediated DDI would be significantly reduced 
      because of saturation of P-gp efflux. The simulation suggested that although 
      drugs with lower permeability were more susceptible, even drugs with higher 
      permeability than metoprolol, a representative highly permeable drug, such as BCS 
      class 1 and 2, may experience DDIs owing to P-gp inhibition. Overall, this study 
      demonstrated the usefulness of mathematical intestinal models when only limited 
      observational data are available.
CI  - Copyright (c) 2017 American Pharmacists Association(R). Published by Elsevier Inc. 
      All rights reserved.
FAU - Ando, Hirotaka
AU  - Ando H
AD  - Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, 
      The University of Tokyo, Tokyo, Japan.
FAU - Hatakeyama, Hiroto
AU  - Hatakeyama H
AD  - Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical 
      Sciences, Chiba University, Chiba, Japan.
FAU - Sato, Hiromi
AU  - Sato H
AD  - Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical 
      Sciences, Chiba University, Chiba, Japan.
FAU - Hisaka, Akihiro
AU  - Hisaka A
AD  - Clinical Pharmacology and Pharmacometrics, Graduate School of Pharmaceutical 
      Sciences, Chiba University, Chiba, Japan. Electronic address: hisaka@chiba-u.jp.
FAU - Suzuki, Hiroshi
AU  - Suzuki H
AD  - Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, 
      The University of Tokyo, Tokyo, Japan.
LA  - eng
PT  - Journal Article
DEP - 20170504
PL  - United States
TA  - J Pharm Sci
JT  - Journal of pharmaceutical sciences
JID - 2985195R
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Pharmaceutical Preparations)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*metabolism
MH  - Caco-2 Cells
MH  - Computer Simulation
MH  - Humans
MH  - *Intestinal Absorption
MH  - Intestinal Mucosa/metabolism
MH  - Metabolic Clearance Rate
MH  - Models, Biological
MH  - Permeability
MH  - Pharmaceutical Preparations/*metabolism
OTO - NOTNLM
OT  - P-glycoprotein
OT  - drug-drug interaction
OT  - intestinal absorption
OT  - modeling and simulation
OT  - physiologically based pharmacokinetic model
OT  - substrate drug
EDAT- 2017/05/10 06:00
MHDA- 2018/05/08 06:00
CRDT- 2017/05/09 06:00
PHST- 2017/02/14 00:00 [received]
PHST- 2017/04/19 00:00 [revised]
PHST- 2017/04/24 00:00 [accepted]
PHST- 2017/05/10 06:00 [pubmed]
PHST- 2018/05/08 06:00 [medline]
PHST- 2017/05/09 06:00 [entrez]
AID - S0022-3549(17)30336-2 [pii]
AID - 10.1016/j.xphs.2017.04.065 [doi]
PST - ppublish
SO  - J Pharm Sci. 2017 Sep;106(9):2771-2779. doi: 10.1016/j.xphs.2017.04.065. Epub 
      2017 May 4.