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 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.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.003913.
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ABBREVIATIONS: KDR, kinase insert domain-containing receptor; ANF, α-naphthoflavone; BNF, β-naphthoflavone; DMSO, dimethyl sulfoxide; LC-RAM, liquid chromatography with radiochemical detection; LC-RAM-MS/MS, liquid chromatography with tandem radiochemical and mass spectrometry; HPLC, high-pressure liquid chromatography; ESI, electrospray ionization; EROD, ethoxyresorufin O-deethylase; ELISA, enzyme-linked immunosorbent assay; CLM, apparent metabolic clearance; CLT, apparent total body plasma clearance; PBS, phosphate-buffered saline; LDH, lactate dehydrogenase; AUC, area under the curve.
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↵1 Current address: Regulatory Affairs International, Merck Research Laboratories, Blue Bell, PA.
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↵2 Current address: Barrier Operations, Merck Manufacturing, West Point, PA.
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↵3 Current address: RAS Analytical, Merck Research Laboratories, West Point, PA.
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↵4 Current address: Drug Metabolism, Amgen, Thousand Oaks, CA.
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↵5 Current address: MAPK, Bristol Myers Squibb, Princeton, NJ.
- Received January 28, 2005.
- Accepted April 12, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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