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Titolo:
Biotransformation of the anti-angiogenic compound SU5416
Autore:
Antonian, L; Zhang, HB; Yang, C; Wagner, G; Shawver, LK; Shet, M; Ogilvie, B; Madan, A; Parkinson, A;
Indirizzi:
SUGEN Inc, S San Francisco, CA 94080 USA SUGEN Inc S San Francisco CA USA94080 Inc, S San Francisco, CA 94080 USA XenoTech LLC, Kansas City, KS USA XenoTech LLC Kansas City KS USAXenoTech LLC, Kansas City, KS USA
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 12, volume: 28, anno: 2000,
pagine: 1505 - 1512
SICI:
0090-9556(200012)28:12<1505:BOTACS>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
ENDOTHELIAL GROWTH-FACTOR; RECEPTOR TYROSINE KINASES; LIVER-MICROSOMES; FACTOR VEGF; CANCER; TUMOR; INHIBITORS; METASTASIS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
19
Recensione:
Indirizzi per estratti:
Indirizzo: Antonian, L SUGEN Inc, 230 E Grand Ave, S San Francisco, CA 94080 USA SUGEN Inc 230 E Grand Ave S San Francisco CA USA 94080 080 USA
Citazione:
L. Antonian et al., "Biotransformation of the anti-angiogenic compound SU5416", DRUG META D, 28(12), 2000, pp. 1505-1512

Abstract

SU5416 [3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one],an inhibitor of VEGF (vascular endothelial growth factor) receptor tyrosine kinase, Flk-1/KDR (fetal liver kinase 1/kinase insert domain-containing receptor), also known as VEGF receptor 2 (VEGFR2) is in advanced clinical trials for treatment of AIDS-related Kaposi's sarcoma and colorectal and nonsmall cell lung cancers. Since this chemical class has not been studied previously with therapeutic intent, the present study was designed to investigate the in vitro metabolism of SU5416 by mouse, rat, dog, monkey, and human liver microsomes and to identify the major metabolites of SU5416. An HPLC procedure was developed and validated to resolve and quantify SU5416 and itsmetabolites. To evaluate the in vitro metabolism of SU5416, pooled liver microsomes from mice, rats, dogs, monkeys, and humans were incubated with SU5416 (25 muM) in the presence of an NADPH-generating system. In the presence of NADPH, mouse, rat, dog, monkey, and human liver microsomes converted SU5416 to at least 12, 9, 9, 7, and 6 polar metabolites, respectively. Microsomal metabolism of SU5416 showed marked species differences in the levels of different metabolites formed. The overall rate of SU5416 metabolism by liver microsomes from the species examined followed the rank order: monkey greater than or equal to mouse approximate to rat > dog > human. Two major metabolites of SU5416 were identified, a hydroxymethyl derivative of SU5416 (M12) and a carboxylic acid derivative of SU5416 (M6), by spectroscopic methods and comparison with authentic compounds. Both of these oxidative metabolites were further metabolized in vivo through glucuronidation. The metabolic fate of SU5416 in microsomes from various species as well as data from in vivo biotransformation in the rat are discussed.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/09/20 alle ore 19:48:20