In vitro ADME phenotyping in drug discovery: current challenges and future solutions.
Drug-metabolizing enzymes and drug transporters are key regulators of drug disposition and pharmacodynamics, which are closely linked to drug efficacy and safety. In this article, current challenges and future solutions to predicting their influence on pharmacokinetics and inter-organ distribution in humans, from data generated during the drug discovery decision-making process, are presented. In vitro phenotyping strategies for drug metabolizing enzymes (eg, CYP3A4, UGT1A1) and transporters (eg, OATP1B1) are offered, including perspectives on a selection of in vitro systems, novel in vitro phenotyping reagents and remaining technology gaps, challenges in extrapolating in vitro data to the in vivo situation, in silico models for the prediction of whether compounds are enzyme or transporter substrates, and the impact of pharmacogenomics.
Williams
J Andrew
JA
Pfizer Global Research and Development, Pharmacokinetics, Dynamics and Metabolism, Ann Arbor, MI 48103, USA. james.williams2@pfizer.com
Bauman
Jonathan
J
Cai
Hongliang
H
Conlon
Kevin
K
Hansel
Steven
S
Hurst
Susan
S
Sadagopan
Nalini
N
Tugnait
Meera
M
Zhang
Liming
L
Sahi
Jasminder
J
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010597:Pharmacogenetics; D010641:Phenotype
D002352:Carrier Proteins; D004798:Enzymes; D004364:Pharmaceutical Preparations