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Gender effects on rat metabolism of AMG 900, an orally available small molecule aurora kinase inhibitor
- Source :
- Drug metabolism letters. 5(4)
- Publication Year :
- 2011
-
Abstract
- AMG 900 is an orally available small molecule that is highly potent and selective as a pan-aurora kinase inhibitor. AMG 900 is currently undergoing phase 1 clinical evaluation in patients with advanced solid tumors. The metabolism of AMG 900 was investigated in both male and female rats. We conducted studies in bile-duct catheterized (BDC) rats where bile, urine and plasma were analyzed to obtain metabolism profiles for each gender. These studies identified gender differences in the metabolism profiles in bile. Bile contained the majority of the drug related material and contained little unchanged AMG 900 which indicated that metabolism was the prominent process in drug elimination. Although bile contained the same metabolites for both genders, the amount of specific metabolites differed. Male rats metabolized AMG 900 primarily through hydroxylation with subsequent sulfate conjugation on the pyrimidinyl-pyridine side-chain whereas female rats favored a different oxidation site on the thiophene ring's methyl group, which is then metabolized to a carboxylic acid with subsequent conjugation to an acyl glucuronide. CYP phenotyping identified the prominent isoforms as being gender specific or biased in the oxidative metabolism of AMG 900. The metabolism in male rats favored both CYP2C11 and CYP2A2 whereas females favored the CYP2C12. The prominent sulfate conjugate identified in the male rat bile could also be due to male biased metabolism since it has been reported that sulfate conjugation is more prevalent in male rats. All the prominent rat metabolism routes for AMG 900 either have male or female bias. These differences in the rat AMG 900 metabolism profiles in bile can be explained by gender specific P450CYP isoforms.
- Subjects :
- Gene isoform
Male
Carboxylic acid
Clinical Biochemistry
Aurora inhibitor
Pharmaceutical Science
Administration, Oral
Urine
Pharmacology
Protein Serine-Threonine Kinases
Hydroxylation
Rats, Sprague-Dawley
chemistry.chemical_compound
Sulfate conjugate
Glucuronides
Sex Factors
Aurora Kinases
Animals
Bile
Pharmacology (medical)
Cytochrome P450 Family 2
Protein Kinase Inhibitors
Biotransformation
chemistry.chemical_classification
biology
Molecular Structure
Kinase
Sulfates
Biochemistry (medical)
Metabolism
Rats
chemistry
Steroid 16-alpha-Hydroxylase
Steroid Hydroxylases
biology.protein
Phthalazines
Female
Aryl Hydrocarbon Hydroxylases
Subjects
Details
- ISSN :
- 18740758
- Volume :
- 5
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Drug metabolism letters
- Accession number :
- edsair.doi.dedup.....63f75b72c0d1242e9aefad88f94aba2a