RT Journal Article
SR Electronic
T1 INDUCTION OF CYP1A IN THE BEAGLE DOG BY AN INHIBITOR OF KINASE INSERT DOMAIN-CONTAINING RECEPTOR: DIFFERENTIAL EFFECTS IN VITRO AND IN VIVO ON MRNA AND FUNCTIONAL ACTIVITY
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1044
OP 1051
DO 10.1124/dmd.105.003913
VO 33
IS 7
A1 Christopher R. Gibson
A1 Charles Lin
A1 Rominder Singh
A1 Cheri M. Brown
A1 Karen Richards
A1 Janice Brunner
A1 Kimberly Michel
A1 Jennifer Adelsberger
A1 Edward Carlini
A1 Catherine Boothe-Genthe
A1 Conrad Raab
A1 Minh Luu
A1 Aimee Michael
A1 Mona Parikh
A1 Patrice Ciecko
A1 Raju Subramanian
A1 Paul Krolikowski
A1 A. David Rodrigues
A1 Thomas A. Baillie
A1 Thomas H. Rushmore
YR 2005
UL http://dmd.aspetjournals.org/content/33/7/1044.abstract
AB Compound I [3-[5-(4-methanesulfonyl-piperazin-1-ylmethyl)-1H-indol-2-yl]-1H-quinolin-2-one] is a potent inhibitor of human kinase insert domain-containing receptor (KDR kinase), which is under investigation for the treatment of cancer. Bile duct-cannulated male beagle dogs were administered 6 mg/kg compound I q.d. for 14 days. There was an approximately 2.5-fold decrease in the mean plasma area under the curve of I on days 7 and 14 (∼11.3 μM · h), relative to day 1 (28.2 μM · h). In the dog, compound I was eliminated by metabolism, with a major pathway being aromatic hydroxylation and subsequent sulfation to form the metabolite M3. Metabolic profiling suggested that the pathway leading to the formation of the sulfated conjugate M3 was induced upon multiple dosing of I. Studies conducted in vitro suggested that CYP1A1/2 was responsible for the formation of the hydroxylated metabolite, which is sulfated to yield M3. Additional studies confirmed induction of CYP1A protein and activity in the livers of dogs treated with I. However, studies in a dog hepatocyte model of induction showed a surprising decrease both in CYP1A mRNA and enzymatic activity in the presence of I, emphasizing the need to consider the results from a variety of in vitro and in vivo studies in deriving an understanding of the metabolic fate of a drug candidate. It is concluded that the autoinduction observed after multiple treatments with compound I occurs since compound I is both an inducer and a substrate for dog CYP1A. The American Society for Pharmacology and Experimental Therapeutics