Metabolism and disposition of oral dabrafenib in cancer patients: Proposed participation of aryl nitrogen in carbon-carbon bond cleavage via decarboxylation following enzymatic oxidation

Drug Metabolism and Disposition

Volumn 41, Issue 12, 2013, Pages 2215-2224

  Bershas, David A ^a   Ouellet, Daniele ^a   Mamaril Fishman, Donna B ^a   Nebot, Noelia ^a   Carson, Stanley W ^a   Blackman, Samuel C ^a   Morrison, Royce A ^b   Adams, Jerry L ^a   Jurusik, Kristen E ^a   Knecht, Dana M ^a   Gorycki, Peter D ^a   Richards Peterson, Lauren E ^a  

^a GLAXOSMITHKLINE   (United States)

^b GlaxoSmithKline ^*  (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CARBON 14; DABRAFENIB; DRUG METABOLITE; HYDROXYDABRAFENIB; NITROGEN; NORDABRAFENIB; UNCLASSIFIED DRUG;

ADULT; AEROBIC METABOLISM; ARTICLE; BILIARY EXCRETION; CANCER PATIENT; DECARBOXYLATION; DRUG BLOOD LEVEL; DRUG DISPOSITION; DRUG ELIMINATION; DRUG HALF LIFE; DRUG METABOLISM; FEMALE; HUMAN; MALE; METABOLITE; NONHUMAN; OXIDATION; PH; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RADIOACTIVITY; RAT; SINGLE DRUG DOSE; TANDEM MASS SPECTROMETRY; ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY; URINARY EXCRETION;

ADMINISTRATION, ORAL; ADULT; CARBON; DECARBOXYLATION; FECES; FEMALE; HALF-LIFE; HUMANS; IMIDAZOLES; MALE; MIDDLE AGED; NEOPLASMS; NITROGEN; OXIDATION-REDUCTION; OXIMES; YOUNG ADULT;

EID: 84888579962     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.113.053785     Document Type: Article

References (16)

1. Adams JL, Dickerson SH, Johnson NW, Kuntz K, Petrov K, Ralph JM, Rheault TR, Schaaf G, Stellwagen J, Tian X et al. (2009) inventors, no given assignee. Benzene sulfonamide thiazole and oxazole compounds. U.S. patent US2009/0298815 A1.
2. Baudet P and Otten C (1970) Étude comparative de la décarboxylation des acides (benzothia-zolyl-2)-acétique, -3-propionique, -glyoxylique et -pyruvique. Helv Chim Acta 53:1683-1693.
3. Chan P, Lovrić J, and Warwicker J (2006) Subcellular pH and predicted pH-dependent features of proteins. Proteomics 6:3494-3501.
4. Code of Federal Regulations (Revised as of April 1, 2013). Radioactive drugs for certain research uses. 21CFR361.1.
5. Dalvie D, Chen W, Zhang C, Vaz AD, Smolarek TA, Cox LM, Lin J, and Obach RS (2008) Pharmacokinetics, metabolism, and excretion of torcetrapib, a cholesteryl ester transfer protein inhibitor, in humans. Drug Metab Dispos 36:2185-2198.
6. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, and Bottomley W, et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417:949-954.
7. Falchook GS, Long GV, Kurzrock R, Kim KB, Arkenau TH, Brown MP, Hamid O, Infante JR, Millward M, and Pavlick AC, et al. (2012) Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 379:1893-1901.
8. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, and Ibrahim N, et al. (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367:1694-1703.
9. Garteiz DA, Hook RH, Walker BJ, and Okerholm RA (1982) Pharmacokinetics and biotransformation studies of terfenadine in man. Arzneimittelforschung 32 (9a):1185-1190.
10. GlaxoSmithKline (2013) Tafinlar (dabrafenib capsules): US prescribing information.
11. Obach RS (2001) Mechanism of cytochrome P4503A4- and 2D6-catalyzed dehydrogenation of ezlopitant as probed with isotope effects using five deuterated analogs. Drug Metab Dispos 29:1599-1607.
12. Prakash C, Wang W, O'Connell T, and Johnson KA (2008) CYP2C8- and CYP3A-mediated C-demethylation of (3-[(4-tert-butylbenzyl)-(pyridine-3-sulfonyl) -amino]-methyl-phenoxy)-acetic acid (CP-533,536), an EP2 receptor-selective prostaglandin E2 agonist: characterization of metabolites by high-resolution liquid chromatography-tandem mass spectrometry and liquid chromatography/mass spectrometry-nuclear magnetic resonance. Drug Metab Dispos 36:2093-2103.
13. Rheault TR, Stellwagen JC, Adjabeng GM, Horenberger KR, Petrov KG, Waterson AG, Dickerson SH, Mook RAJ, Laquerre SG, and King AJ, et al. (2013) Discovery of dabrafenib: a selective inhibitor of Raf kinases with antitumor activity against B-Raf-driven tumors. ACS Med Chem Lett 4:358-362.
14. Richards-Peterson LE, Wilde TC, Mamaril-Fishman DB, Bershas DA, Karlinsey MZ, Schubert EM, Castellino S, Ouellet D, and Gorycki PD (2013) Disposition and Metabolism of [14C] Dabrafenib, a Raf Kinase Inhibitor, in Mice, Rats, Dogs and Humans. Drug Metab Rev 45:313.
15. Rubinstein JC, Sznol M, Pavlick AC, Ariyan S, Cheng E, Bacchiocchi A, Kluger HM, Narayan D, and Halaban R (2010) Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med 8:67.
16. Yoo HH, Chung HJ, Lee J, Lee CS, Kang MJ, and Kim DH (2008) Enzymatic C-demethylation of 1-[2-(5-tert-butyl-[1,3,4] oxadiazole-2-carbonyl)-4-fluoro- pyrrolidin-1-yl]-2-(2-hydroxy-1,1-dimethyl-ethylamino)-ethanone (LC15-0133) in rat liver microsomes. Drug Metab Dispos 36:485-489.