Abstract
(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514) is a potent inhibitor of ErbB human epidermal growth factor receptors (HER1, 2, and 4) and vascular endothelial growth factor receptors 1 to 3 that has been under clinical development for solid tumor malignancies. BMS-690514 is primarily cleared by metabolism with the primary metabolic pathways being direct glucuronidation (M6), hydroxylation (M1, M2, and M37), and O-demethylation (M3). In the current investigation, the metabolic drug-drug interaction potential of BMS-690514 was evaluated in a series of in vitro studies. Reaction phenotyping experiments with cDNA-expressed human cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) enzymes and human liver microsomes (HLM) in the presence of P450 or UGT inhibitors suggested that CYP3A4, CYP2D6, and CYP2C9 were the major enzymes responsible for the oxidative metabolism of BMS-690514, whereas both UGT2B4 and UGT2B7 were responsible for the formation of M6. BMS-690514 did not cause direct or time-dependent inhibition of P450 enzymes (IC50 values ≥40 μM) in incubations with HLM and probe substrates of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4. The compound also did not substantially induce CYP1A1, CYP1A2, CYP2B6, CYP3A4, or UGT1A1 at concentrations up to 10 μM in cultured human hepatocytes. Considering the submicromolar plasma Cmax concentration at the anticipated clinical dose of 200 mg, BMS-690514 is unlikely to cause clinically relevant drug-drug interactions when coadministered with other medications. In addition, because multiple enzymatic clearance pathways are available for the compound, inhibition of an individual metabolic pathway either via coadministered drugs or gene polymorphisms is not expected to cause pronounced (>2-fold) increases in BMS-690514 exposure.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039776.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- BMS-690514
- (3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol)
- ErbB
- human epidermal growth factor receptors
- VEGFR
- vascular endothelial growth factor receptor
- ADME
- absorption, distribution, metabolism and excretion
- P450
- cytochrome P450
- DDI
- drug-drug interactions
- UGT
- UDP-glucuronosyltransferase
- HLM
- human liver microsome(s)
- BMS-204352
- (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one
- ABT
- 1-aminobenzotriazole
- UDPGA
- UDP-glucuronic acid
- HDCA
- hyodeoxycholic acid
- HPLC
- high-performance liquid chromatography
- DMSO
- dimethyl sulfoxide
- IS
- internal standard
- LC
- liquid chromatography
- MS/MS
- tandem spectrometry
- MRM
- multiple reaction monitoring
- 3-MC
- 3-methylcholanthrine
- LDH
- lactate dehydrogenase.
- Received March 27, 2011.
- Accepted June 14, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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