PMID- 17191947
OWN - NLM
STAT- MEDLINE
DCOM- 20070222
LR  - 20061228
IS  - 1612-1880 (Electronic)
IS  - 1612-1872 (Linking)
VI  - 2
IP  - 11
DP  - 2005 Nov
TI  - Development and application of physiologically based pharmacokinetic-modeling 
      tools to support drug discovery.
PG  - 1462-86
AB  - Physiologically based pharmacokinetic (PBPK) modeling integrates physicochemical 
      (PC) and in vitro pharmacokinetic (PK) data using a mechanistic framework of 
      principal ADME (absorption, distribution, metabolism, and excretion) processes 
      into a physiologically based whole-body model. Absorption, distribution, and 
      clearance are modeled by combining compound-specific PC and PK properties with 
      physiological processes. Thereby, isolated in vitro data can be upgraded by means 
      of predicting full concentration-time profiles prior to animal experiments. The 
      integrative process of PBPK modeling leads to a better understanding of the 
      specific ADME processes driving the PK behavior in vivo, and has the power to 
      rationally select experiments for a more focussed PK project support. This 
      article presents a generic disposition model based on tissue-composition-based 
      distribution and directly scaled hepatic clearance. This model can be used in 
      drug discovery to identify the critical PK issues of compound classes and to 
      rationally guide the optimization path of the compounds toward a viable 
      development candidate. Starting with a generic PBPK model, which is empirically 
      based on the most common PK processes, the model will be gradually tailored to 
      the specifics of drug candidates as more and more experimental data become 
      available. This will lead to a growing understanding of the 'drug in the making', 
      allowing a range of predictions to be made for various purposes and conditions. 
      The stage is set for a wide penetration of PK modeling and simulations to form an 
      intrinsic part of a project starting from lead discovery, to lead optimization 
      and candidate selection, to preclinical profiling and clinical trials.
FAU - Lupfert, Christian
AU  - Lupfert C
AD  - Research Pharmacokinetics, Schering AG, Mullerstrasse 178, D-13342 Berlin.
FAU - Reichel, Andreas
AU  - Reichel A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Switzerland
TA  - Chem Biodivers
JT  - Chemistry & biodiversity
JID - 101197449
RN  - 0 (Pharmaceutical Preparations)
SB  - IM
MH  - Drug Evaluation, Preclinical/methods
MH  - Metabolic Clearance Rate/physiology
MH  - Metabolic Networks and Pathways/physiology
MH  - *Models, Biological
MH  - *Models, Chemical
MH  - Pharmaceutical Preparations/chemistry/*metabolism
MH  - *Pharmacokinetics
MH  - Technology, Pharmaceutical/*trends
MH  - Tissue Distribution/physiology
EDAT- 2006/12/29 09:00
MHDA- 2007/02/23 09:00
CRDT- 2006/12/29 09:00
PHST- 2006/12/29 09:00 [pubmed]
PHST- 2007/02/23 09:00 [medline]
PHST- 2006/12/29 09:00 [entrez]
AID - 10.1002/cbdv.200590119 [doi]
PST - ppublish
SO  - Chem Biodivers. 2005 Nov;2(11):1462-86. doi: 10.1002/cbdv.200590119.