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Titolo:
In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6
Autore:
Ko, JW; Desta, Z; Soukhova, NV; Tracy, T; Flockhart, DA;
Indirizzi:
Georgetown Univ, Med Ctr, Div Clin Pharmacol, Dept Med, Washington, DC 20007 USA Georgetown Univ Washington DC USA 20007 ept Med, Washington, DC 20007 USA Georgetown Univ, Med Ctr, Div Clin Pharmacol, Dept Pharmacol, Washington, DC 20007 USA Georgetown Univ Washington DC USA 20007 armacol, Washington, DC 20007 USA W Virginia Univ, Sch Pharm, Morgantown, WV 26506 USA W Virginia Univ Morgantown WV USA 26506 h Pharm, Morgantown, WV 26506 USA
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 4, volume: 49, anno: 2000,
pagine: 343 - 351
SICI:
0306-5251(200004)49:4<343:IVIOTC>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER; PHENYTOIN METABOLISM; IN-VITRO; PHARMACOKINETICS; HYDROXYLATION; TOLBUTAMIDE; MEPHENYTOIN; MICROSOMES; OMEPRAZOLE; PREVENTION;
Keywords:
antiplatelet; cytochrome P450; inhibition; ticlopidine;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
46
Recensione:
Indirizzi per estratti:
Indirizzo: Flockhart, DA Georgetown Univ, Med Ctr, Div Clin Pharmacol, Dept Med, 3900Reservoir Rd NW, Washington, DC 20007 USA Georgetown Univ 3900 Reservoir Rd NW Washington DC USA 20007
Citazione:
J.W. Ko et al., "In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6", BR J CL PH, 49(4), 2000, pp. 343-351

Abstract

Aims To examine the potency of ticlopidine (TCL) as an inhibitor of cytochrome P450s (CYP450s) in vitro using human liver microsomes (HLMs) and recombinant human CYP450s. Methods Isoform-specific substrate probes of CYP1A2, 2C19, 2C9, 2D6, 2E1 and 3A4 were incubated in HLMs or recombinant CYPs with or without TCL. Preliminary data were generated to simulate an appropriate range of substrate and inhibitor concentrations to construct Dixon plots. In order to estimate accurately inhibition constants (K-i values) of TCL and determine the type of inhibition, data from experiments with three different HLMs for each isoform were fitted to relevant nonlinear regression enzyme inhibition models by WinNonlin. Results TCL was a potent, competitive inhibitor of CYP2C19 (K-i = 1.2 +/- 0.5 mu m) and of CYP2D6 (K-i = 3.4 +/- 0.3 mu m). These K-i values fell within the therapeutic steady-state plasma concentrations of TCL (1-3 mu m). TCL was also a moderate inhibitor of CYP1A2 (K-i = 49 +/- 19 mu m) and a weak inhibitor of CYP2C9 (K-i > 75 mu m), but its effect on the activities of CYP2E1 (K-i = 584 +/- 48 mu m) and CYP3A (> 1000 mu m) was marginal. Conclusions TCL appears to be a broad-spectrum inhibitor of the CYP isoforms, but clinically significant adverse drug interactions are most likely with drugs that are substrates of CYP2C19 or CYP2D6.

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Documento generato il 28/01/20 alle ore 20:56:05