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Titolo:
Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: Potent inhibition of CYP2C19 and CYP3A
Autore:
Desta, Z; Soukhova, NV; 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
Titolo Testata:
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
fascicolo: 2, volume: 45, anno: 2001,
pagine: 382 - 392
SICI:
0066-4804(200102)45:2<382:IOCP(I>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER; IN-VITRO; DRUG-METABOLISM; DIPHENYLHYDANTOIN INTOXICATION; ACTIVE TUBERCULOSIS; OMEPRAZOLE; PHENYTOIN; HEPATOTOXICITY; MICROSOMES; OXIDATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
61
Recensione:
Indirizzi per estratti:
Indirizzo: Desta, Z Georgetown Univ, Med Ctr, Div Clin Pharmacol, Dept Med, 3900 Reservoir Rd NW,Med Dent Bldg,Room SE408, Washington, DC 20007 USA Georgetown Univ 3900 Reservoir Rd NW,Med Dent Bldg,Room SE408 Washington DC USA 20007
Citazione:
Z. Desta et al., "Inhibition of cytochrome P450 (CYP450) isoforms by isoniazid: Potent inhibition of CYP2C19 and CYP3A", ANTIM AG CH, 45(2), 2001, pp. 382-392

Abstract

Isoniazid (INN) remains the most safe and cost-effective drug for the treatment and prophylaxis of tuberculosis. The use of INH has increased over the past years, largely as a result of the coepidemic of human immunodeficiency virus infection. It is frequently given chronically to critically ill patients who are coprescribed multiple medications. The ability of INH to elevate the concentrations in plasma and/or toxicity of coadministered drugs, including those of narrow therapeutic range (e.g., phenytoin), has been documented in humans, but the mechanisms involved are not well understood. Using human liver microsomes (HLMs), we tested the inhibitory effect of INH onthe activity of common drug-metabolizing human cytochrome P450 (CYP450) isoforms using isoform-specific substrate probe reactions. Incubation experiments were performed at a single concentration of each substrate probe at its K-m value with a range of INH concentrations. CYP2C19 and CYP3A were inhibited potently by INH in a concentration-dependent manner. At 50 muM INH (similar to6.86 mug/ml), the activities of these isoforms decreased by similar to 40%. INH did not show significant inhibition (<10% at 50 <mu>M) of other isoforms (CYP2C9, CYP1A2, and CYP2D6). To accurately estimate the inhibition constants (K-i values) for each isoform, four concentrations of INH were incubated across a range of five concentrations of specific substrate probes. The mean K-i values (+/- standard deviation) for the inhibition of CYP2C19 by INH in HLMs and recombinant human CYP2C19 were 25.4 +/- 6.2 and 13+/- 2.4 muM, respectively. INH showed potent noncompetitive inhibition of CYP3A (K-i = 51.8 +/- 2.5 to 75.9 +/- 7.8 muM, depending on the substrate used). INH was a weak noncompetitive inhibitor of CYP2E1 (K-i = 110 +/- 33 muM) and a competitive inhibitor of CYP2D6 (K-i = 126 +/- 23 muM), but the mean K-i values for the inhibition of CYP2C9 and CYP1A2 were above 500 muM. Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone. Slow acetylatorsof INH may be at greater risk for adverse drug interactions, as the degreeof inhibition was concentration dependent. These data provide a rational basis for understanding drug interaction with INH and predict that other drugs metabolized by these two enzymes may also interact.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 06:16:44