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Titolo:
In vitro high throughput screening of compounds for favorable metabolic properties in drug discovery
Autore:
Masimirembwa, CM; Thompson, R; Andersson, TB;
Indirizzi:
AstraZeneca, R&D Molndal, Dept DMPK & Bioanalyt Chem, S-43183 Molndal, Sweden AstraZeneca Molndal Sweden S-43183 oanalyt Chem, S-43183 Molndal, Sweden
Titolo Testata:
COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
fascicolo: 3, volume: 4, anno: 2001,
pagine: 245 - 263
SICI:
1386-2073(200105)4:3<245:IVHTSO>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
ARYL-HYDROCARBON RECEPTOR; HUMAN LIVER-MICROSOMES; ULTRAFILTRATION-MASS-SPECTROMETRY; HUMAN CYTOCHROME-P450 ENZYMES; PREGNANE X RECEPTOR; IN-VITRO; LIQUID-CHROMATOGRAPHY; HUMAN HEPATOCYTES; GENE INDUCTION; S-MEPHENYTOIN;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
108
Recensione:
Indirizzi per estratti:
Indirizzo: Masimirembwa, CM AstraZeneca, R&D Molndal, Dept DMPK & Bioanalyt Chem, S-43183 Molndal, Sweden AstraZeneca Molndal Sweden S-43183 3183 Molndal, Sweden
Citazione:
C.M. Masimirembwa et al., "In vitro high throughput screening of compounds for favorable metabolic properties in drug discovery", COMB CHEM H, 4(3), 2001, pp. 245-263

Abstract

Drug metabolism can have profound effects on the pharmacological and toxicological profile of therapeutic agents. In the pharmaceutical industry, many in vitro techniques are in place or under development to screen and optimize compounds for favorable metabolic properties in the drug discovery phase. These in vitro technologies are meant to address important issues such as: (1) is the compound a potent inhibitor of drug metabolising enzymes (DMEs)? (2) does the compound induce the expression of DMEs? (3) how labile is the compound to metabolic degradation? (4) which specific enzyme(s) is responsible for the compound's biotransformation? and (5) to which metabolites is the compound metabolized? Answers to these questions provide a basis forjudging whether a compound is likely to have acceptable pharmacokinetic properties in vivo. To address these issues on the increasing number of compounds inundating the drug discovery programs, high throughput assays are essential. A combination of biochemical advances in the understanding of the function and regulation of DMEs (in particular, cytochromes P450, CYPs) and automated analytical technologies are revolutionizing drug metabolism research. Automated LC-MS based metabolic stability, fluorescence, radiometric and LC-MS based CYP inhibition assays are now in routine use. Automatible models for studying CYP induction based on enzyme activity, quantitative RT-PCR and reporter gene systems are being developed. We will review the utility and limitations of these HTS approaches and highlight on-going developments and emerging technologies to answer metabolism questions at the different stages of the drug discovery process.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 08/04/20 alle ore 10:42:30