PMID- 23358262
OWN - NLM
STAT- MEDLINE
DCOM- 20140429
LR  - 20191227
IS  - 1880-0920 (Electronic)
IS  - 1347-4367 (Linking)
VI  - 28
IP  - 4
DP  - 2013
TI  - Three-dimensional quantitative structure-activity relationship analysis of 
      inhibitors of human and rat cytochrome P4503A enzymes.
PG  - 345-55
AB  - Cytochrome P450 3A4 (CYP3A4) is a member of the CYP family and is an important 
      enzyme in drug metabolism. A compound that inhibits CYP3A4 activity could also 
      affect the pharmacokinetics of other substrates, resulting in drug-drug 
      interactions (DDIs) that could cause side effects. Pharmacokinetic data from 
      drug-development studies in rats often determine the dosage used in human 
      clinical trials. It is therefore useful to understand differences in metabolism 
      in different species at an early stage in drug development. Human and rat CYP3A 
      enzymes show different inhibition profiles with different drugs, although the 
      mechanisms involved are not yet clear. Here we built three-dimensional 
      quantitative structure-activity relationship (3D-QSAR) models using 
      structure-based comparative molecular field analysis (CoMFA), to predict the 
      direct inhibitory activity of ligands for human CYP3A4 and rat CYP3A1, based on 
      computer-ligand docking. The alignment of the ligand docking poses suggested that 
      key amino acid-ligand interactions (e.g., Thr309 in CYP3A4 and Pro310 in CYP3A1) 
      characterized the different potencies with which the ligands inhibited CYP3A4 and 
      CYP3A1. The 3D-QSAR models for human and rat CYP3A family inhibitors predicted 
      the potency of inhibitors and could be useful for assessing DDIs at an early 
      stage in drug discovery.
FAU - Handa, Koichi
AU  - Handa K
AD  - School of Pharmacy, Kitasato University, Tokyo, Japan. 
      KOICHI_HANDA@toyama-chemical.co.jp
FAU - Nakagome, Izumi
AU  - Nakagome I
FAU - Yamaotsu, Noriyuki
AU  - Yamaotsu N
FAU - Gouda, Hiroaki
AU  - Gouda H
FAU - Hirono, Shuichi
AU  - Hirono S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130129
PL  - England
TA  - Drug Metab Pharmacokinet
JT  - Drug metabolism and pharmacokinetics
JID - 101164773
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - 0 (Ligands)
RN  - 8VZV102JFY (Fluconazole)
RN  - EC 1.14.14.1 (Cyp3a23-3a1 protein, rat)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
RN  - L3JE09KZ2F (Saquinavir)
RN  - O3J8G9O825 (Ritonavir)
RN  - O4L1XPO44W (Fluvoxamine)
SB  - IM
MH  - Animals
MH  - Cytochrome P-450 CYP3A
MH  - *Cytochrome P-450 CYP3A Inhibitors
MH  - Drug Interactions
MH  - Fluconazole/pharmacology
MH  - Fluvoxamine/pharmacology
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Ligands
MH  - Models, Molecular
MH  - Molecular Docking Simulation
MH  - Quantitative Structure-Activity Relationship
MH  - Rats
MH  - Ritonavir/pharmacology
MH  - Saquinavir/pharmacology
EDAT- 2013/01/30 06:00
MHDA- 2014/04/30 06:00
CRDT- 2013/01/30 06:00
PHST- 2013/01/30 06:00 [entrez]
PHST- 2013/01/30 06:00 [pubmed]
PHST- 2014/04/30 06:00 [medline]
AID - DN/JST.JSTAGE/dmpk/DMPK-12-RG-133 [pii]
AID - 10.2133/dmpk.dmpk-12-rg-133 [doi]
PST - ppublish
SO  - Drug Metab Pharmacokinet. 2013;28(4):345-55. doi: 10.2133/dmpk.dmpk-12-rg-133. 
      Epub 2013 Jan 29.