Received for publication January 31, 2005.
Revised April 8, 2005.
Accepted for publication April 12, 2005.

INDUCTION OF CYP1A IN THE BEAGLE DOG BY AN INHIBITOR OF KDR KINASE: DIFFERENTIAL EFFECTS IN VITRO AND IN VIVO ON MRNA AND FUNCTIONAL ACTIVITY

Abstract

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 of compound I q.d. for fourteen days. There was an approximate 2.5-fold decrease in the mean plasma area under the curve (AUC) of I on days 7 and 14 (~11.3 µM*hr), relative to day 1 (28.2 µM*hr). 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 substrate for dog CYP1A.

Key words: anticancer agents, CYP induction, CYP1A, enzyme induction, induction, pharmacokinetics

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