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Titolo:
In vitro inhibition and induction of human hepatic cytochrome P450 enzymesby modafinil
Autore:
Robertson, P; Decory, HH; Madan, A; Parkinson, A;
Indirizzi:
Cephalon Inc, Dept Drug Safety & Disposit, W Chester, PA 19380 USA Cephalon Inc W Chester PA USA 19380 y & Disposit, W Chester, PA 19380 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: 6, volume: 28, anno: 2000,
pagine: 664 - 671
SICI:
0090-9556(2000)28:6<664:IVIAIO>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; RAT HEPATOCYTES; IN-VITRO; METABOLISM; IDENTIFICATION; CLOMIPRAMINE; MEPHENYTOIN; OXIDATION; BIOTRANSFORMATION; HYDROXYLATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Robertson, P Cephalon Inc, Dept Drug Safety & Disposit, 145 Brandywine Pkwy, W Chester,PA 19380 USA Cephalon Inc 145 Brandywine Pkwy W Chester PA USA19380 0 USA
Citazione:
P. Robertson et al., "In vitro inhibition and induction of human hepatic cytochrome P450 enzymesby modafinil", DRUG META D, 28(6), 2000, pp. 664-671

Abstract

The ability of modafinil to affect human hepatic cytochrome P450 (CYP) activities was examined in vitro. The potential for inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 by modafinil (5-250 mu M) was evaluated with pooled human liver microsomes. Modafinil exhibited minimal capacity to inhibit any CYP enzyme, except CYP2C19. Modafinil inhibited the 4'-hydroxylation of S-mephenytoin, a marker substrate for CYP2C19, reversibly and competitively with a K-i value of 39 mu M, which approximates the steady-state C-max value of modafinil in human plasmaat a dosage of 400 mg/day. No irreversible inhibition of any CYP enzyme was observed, and there was no evidence of metabolism-dependent inhibition. The potential for induction of CYP activity was evaluated by exposing primary cultures of human hepatocytes to modafinil (10-300 mu M). Microsomes werethen prepared and assayed for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 activities. The mean activities of microsomal CYP1A2, CYP2B6, and CYP3A4/5 from modafinil-treated hepatocytes were higher (up to 2-fold) than those in the solvent-treated controls but were less than those produced by reference inducers of these enzymes. At high concentrations of modafinil (greater than or equal to 100 mu M), the mean activity of CYP2C9 was decreased (up to 60%) relative to that in the solvent controls. Overall, modafinil was shown to have effects on human hepatic CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 activities in vitro. Although effects obtained in vitro are not always predictive of effects in vivo, such results provide a rational basis for understanding drug-drug interactions that are observed clinically and for planning subsequent investigations.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/09/20 alle ore 21:35:28