High-throughput evaluation of CYP1A1 and 2B1 induction in rat liver slices using a semi-automated system.
Drug candidates with the propensity to induce rat CYP1A1 or 2B1 isoforms are believed to possess a greater tendency to induce hepatic tumors in oncogenicity studies. We have previously published on a manual rat liver slice assay that showed a satisfactory relationship between in vitro CYP2B1 m-RNA induction using real time PCR and the ex vivo pentoxyresorufin O-dealkylase (PROD) activity in liver microsomes prepared from rats treated daily via the oral route for 14 consecutive days with inducers or non-inducers. We now describe this automated in vitro high throughput liver slice technique to screen out drug candidates that are potent rodent CYP1A1 and/or CYP2B1 inducers. A good concordance between in vitro and in vivo data was observed for both CYP1A1 (100 %) and CYP2B1 (90%) isoforms. Automation of key steps has enabled us to increase the annual screening throughput from 200 (manual) to 1500 compounds. The increase in throughput allowed the quick development of structure-induction relationships (SIR's) for multiple drug discovery programs in a facile manner.
Palamanda
Jairam R
JR
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. Jairam.Palamanda@spcorp.com
Lin
Xinjie
X
Kumari
Pramila
P
Nomeir
Amin A
AA
D000284:Administration, Oral; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects* / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000187:drug effects* / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods; D004790:Enzyme Induction / Q000187:drug effects*; D008099:Liver / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D012333:RNA, Messenger; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1