Gender effects on rat metabolism of AMG 900, an orally available small molecule aurora kinase inhibitor.
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.
Pharmacokinetics and Drug Metabolism, Amgen, Inc., Cambridge, MA 02142, USA.
Daniel
D
Waldon
Loren
L
Berry
Min-Hwa Jasmine
MH
Lin
Laurie
L
Schenkel
L Steven
LS
Hollis
Zhiyang
Z
Zhao
D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D064127:Aurora Kinases; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D000072467:Cytochrome P450 Family 2; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D006900:Hydroxylation; D008297:Male; D015394:Molecular Structure; D010793:Phthalazines / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000378:metabolism; D013431:Sulfates / Q000378:metabolism
D020719:Glucuronides; C555658:N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D013431:Sulfates; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; C034694:steroid 15-beta-hydroxylase; C029009:steroid hormone 7-alpha-hydroxylase; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases