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.
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 (approximately 11.3 microM . h), relative to day 1 (28.2 microM . 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.
Gibson
Christopher R
CR
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA. Christopher_Gibson@merck.com
Lin
Charles
C
Singh
Rominder
R
Brown
Cheri M
CM
Richards
Karen
K
Brunner
Janice
J
Michel
Kimberly
K
Adelsberger
Jennifer
J
Carlini
Edward
E
Boothe-Genthe
Catherine
C
Raab
Conrad
C
Luu
Minh
M
Michael
Aimee
A
Parikh
Mona
M
Ciecko
Patrice
P
Subramanian
Raju
R
Krolikowski
Paul
P
Rodrigues
A David
AD
Baillie
Thomas A
TA
Rushmore
Thomas H
TH
D000818:Animals; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D017931:DNA Primers; D004285:Dogs; D004790:Enzyme Induction; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*
D017931:DNA Primers; D047428:Protein Kinase Inhibitors; D019363:Cytochrome P-450 CYP1A1