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Titolo:
Interaction of cisapride with the human cytochrome P450 system: Metabolismand inhibition studies
Autore:
Desta, Z; Soukhova, N; Mahal, SK; 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:
DRUG METABOLISM AND DISPOSITION
fascicolo: 7, volume: 28, anno: 2000,
pagine: 789 - 800
SICI:
0090-9556(200007)28:7<789:IOCWTH>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER; IN-VITRO; DRUG-INTERACTIONS; PROKINETIC AGENT; QT INTERVAL; VIVO; BROMPERIDOL; MIDAZOLAM; FRACTIONS; SUBFAMILY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
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., "Interaction of cisapride with the human cytochrome P450 system: Metabolismand inhibition studies", DRUG META D, 28(7), 2000, pp. 789-800

Abstract

Using human liver microsomes (HLMs) and recombinant cytochrome P450s (CYP450s), we characterized the CYP450 isoforms involved in the primary metabolic pathways of cisapride and documented the ability of cisapride to inhibit the CYP450 system. In HLMs, cisapride was N-dealkylated to norcisapride (NORCIS) and hydroxylated to 3-fluoro-4-hydroxycisapride (3-F-4-OHCIS) and to 4-fluoro-2-hydroxycisapride (4-F-2-OHCIS). Formation of NORCIS, 3-F-4-OHCIS, and 4-F-2-OHCIS in HLMs exhibited Michaelis-Menten kinetics (K-m : 23.4 +/- 8.6, 32 +/- 11, and 31 +/- 23 mM; V-max : 155 +/- 91, 52 +/- 23, and 31 /- 23 pmol/min/mg of protein, respectively). The average in vitro intrinsic clearance (V-max/K-m) revealed that the formation of NORCIS was 3.9- to 5.9-fold higher than that of the two hydroxylated metabolites. Formation rate of NORCIS from 10 mM cisapride in 14 HLMs was highly variable (range, 4.9-133.6 pmol/min/mg of protein) and significantly correlated with the activities of CYP3A (r = 0.86, P = .0001), CYP2C19, and 1A2. Of isoform-specific inhibitors, 1 mM ketoconazole and 50 mM troleandomycin were potent inhibitors of NORCIS formation from 10 mM cisapride (by 51 +/- 9 and 44 +/- 17%, respectively), whereas the effect of other inhibitors was minimal. Of 10 recombinant human CYP450s tested, CYP3A4 formed NORCIS from 10 mM cisapride at the highest rate (V = 0.56 +/- 0.13 pmol/min/pmol of P450) followed by CYP2C8 (V = 0.29 +/- 0.08 pmol/min/pmol of P450) and CYP2B6 (0.15 +/- 0.04 pmol/min/pmol of P450). The formation of 3-F-4-OHCIS was mainly catalyzed by CYP2C8 (V = 0.71 +/- 0.24 pmol/min/pmol of P450) and that of 4-F-2-OHCIS by CYP3A4 (0.16 +/- 0.03 pmol/min/pmol of P450). Clearly, recombinant CYP2C8 participates in cisapride metabolism, but when the in vitro intrinsic clearances obtained were corrected for abundance of each CYP450 in the liver, CYP3A4 is the dominant isoform. Cisapride was a relatively potent inhibitor of CYP2D6, with no significant effect on other isoforms tested, but the K-i value derived (14 +/- 16 mM) was much higher than the clinically expected concentration of cisapride (< 1 mM). Our data suggest that CYP3A is the main isoform involved in the overall metabolic clearance of cisapride. Cisapride metabolism is likely to be subject to interindividual variability in CYP3A expression and to drug interactions involving this isoform.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 15:43:27