PMID- 22912432
OWN - NLM
STAT- MEDLINE
DCOM- 20130612
LR  - 20181202
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 40
IP  - 11
DP  - 2012 Nov
TI  - Utility of DPX2 cells for predicting CYP3A induction-mediated drug-drug 
      interactions and associated structure-activity relationships.
PG  - 2204-11
LID - 10.1124/dmd.112.047456 [doi]
AB  - The increase in cytochrome P450 (P450) enzyme activity noted upon exposure to 
      therapeutics can elicit marked drug-drug interactions (DDIs) that may ultimately 
      result in poor clinical outcome or adverse drug effects. As such, in vitro model 
      systems that can rapidly and accurately determine whether potential therapeutics 
      activate the human pregnane X receptor (PXR) and thus induce CYP3A P450 levels 
      are highly sought after tools for drug discovery. To that end, we assessed 
      whether DPX2 cells, a HepG2-derived cell line stably integrated with a PXR 
      expression vector plus a luciferase reporter, could detect agents that not only 
      cause PXR activation/CYP3A induction but also elicit clinical DDIs. All 20 
      clinical inducers and 9 of 15 clinical noninducers examined activated PXR in DPX2 
      cells (E(max) > 8-fold), although activation parameters obtained with the 
      noninducers were not predictive of DDI. The relative induction score, calculated 
      by combining PXR activation parameters (EC(50) and E(max)) in DPX2 cells for 
      seven inducers plus four noninducers with their efficacious total plasma 
      concentrations, strongly correlated (R(2) = 0.90) with the magnitude of induction 
      of midazolam clearance. Thus, the DPX cell-based PXR activation system is not 
      only capable of distinguishing potential inducers in a high-throughput manner but 
      can also differentiate among compounds in predicting the magnitude of 
      induction-mediated DDIs, providing a means for structure-activity relationship 
      screening during discovery and development.
FAU - Fahmi, Odette A
AU  - Fahmi OA
AD  - Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc., Global 
      Research and Development, Groton, CT 06340, USA. odette.a.fahmi@pfizer.com
FAU - Raucy, Judy L
AU  - Raucy JL
FAU - Ponce, Elsa
AU  - Ponce E
FAU - Hassanali, Saleema
AU  - Hassanali S
FAU - Lasker, Jerome M
AU  - Lasker JM
LA  - eng
PT  - Journal Article
DEP - 20120821
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Pregnane X Receptor)
RN  - 0 (Receptors, Steroid)
RN  - EC 1.14.14.1 (CYP3A protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - R60L0SM5BC (Midazolam)
SB  - IM
MH  - Cell Line, Tumor
MH  - Cytochrome P-450 CYP3A/biosynthesis/*metabolism
MH  - Drug Interactions
MH  - Enzyme Induction
MH  - Hep G2 Cells
MH  - Humans
MH  - Midazolam/metabolism
MH  - Pregnane X Receptor
MH  - Receptors, Steroid/metabolism
MH  - Structure-Activity Relationship
EDAT- 2012/08/23 06:00
MHDA- 2013/06/13 06:00
CRDT- 2012/08/23 06:00
PHST- 2012/08/23 06:00 [entrez]
PHST- 2012/08/23 06:00 [pubmed]
PHST- 2013/06/13 06:00 [medline]
AID - dmd.112.047456 [pii]
AID - 10.1124/dmd.112.047456 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2012 Nov;40(11):2204-11. doi: 10.1124/dmd.112.047456. Epub 
      2012 Aug 21.