Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
IDENTIFICATION AND CHARACTERIZATION OF HUMAN CYTOCHROME-P450 ISOFORMSINTERACTING WITH PIMOZIDE
Autore:
DESTA Z; KERBUSCH T; SOUKHOVA N; RICHARD E; KO JW; FLOCKHART DA;
Indirizzi:
GEORGETOWN UNIV,MED CTR,DIV CLIN PHARMACOL,DEPT MED & PHARMACOL,3900 RESERVOIR RD NW WASHINGTON DC 20007 GEORGETOWN UNIV,MED CTR,DIV CLIN PHARMACOL,DEPT MED & PHARMACOL WASHINGTON DC 20007
Titolo Testata:
The Journal of pharmacology and experimental therapeutics
fascicolo: 2, volume: 285, anno: 1998,
pagine: 428 - 437
SICI:
0022-3565(1998)285:2<428:IACOHC>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; TOURETTES-SYNDROME; DRUG-INTERACTIONS; N-DEMETHYLATION; S-MEPHENYTOIN; IN-VITRO; DEXTROMETHORPHAN; HYDROXYLATION; INHIBITORS; METABOLISM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
54
Recensione:
Indirizzi per estratti:
Citazione:
Z. Desta et al., "IDENTIFICATION AND CHARACTERIZATION OF HUMAN CYTOCHROME-P450 ISOFORMSINTERACTING WITH PIMOZIDE", The Journal of pharmacology and experimental therapeutics, 285(2), 1998, pp. 428-437

Abstract

Using human liver microsomes (HLMs) and recombinant human cytochrome P450 (CYP450) isoforms, we identified the major route of pimozide metabolism, the CYP450 isoforms involved, and documented the inhibitory effect of pimozide on CYP450 isoforms. Pimozide was predominantly N-dealkylated to 1,3-dihydro-1 -(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI). The formation rate of DHPBI showed biphasic kinetics in HLMs, whichsuggests the participation of at least two activities. These were characterized as high-affinity (K-m1 and V-max1) and low-affinity (K-m2 and V-max2) components. The ratio of V-max1(14 pmol/min/mg protein)/K-m1,, (0.73 mu M) was 5.2 times higher than the ratio of V-max2 (244 pmol/min/mg protein)/K-m2 (34 mu M). K-m2 was 91 times higher than K-m1. The formation rate of DHPBI from 25 mu M pimozide in nine human liverscorrelated significantly with the catalytic activity of CYP3A (Spearman r = 0.79, P = .028), but not with other isoforms. Potent inhibitionof DHPBI formation from 10 mu M pimozide was observed with ketoconazole (88%), troleandomycin (79%), furafylline (48%) and a combination offurafylline and ketoconazole (96%). Recombinant human CYP3A4 catalyzed DHPBI formation from 10 mu M pimozide at the highest rate (V = 2.2 +/- 0.89 pmol/min/pmol P450) followed by CYP1A2 (V = 0.23 +/- 0.08 pmol/min/pmol P450), but other isoforms tested did not. The K-m, values derived with recombinant CYP3A4 and CYP1A2 were 5.7 mu M and 36.1 mu M, respectively. Pimozide itself was a potent inhibitor of CYP2D6 in HLMswhen preincubated for 15 min (K-l = 0.75 +/- 0.98 mu M) and a moderate inhibitor of CYP3A (K-l = 76.7 +/- 34.5 mu M), with no significant effect on other isoforms tested. Our results suggest that pimozide metabolism is catalyzed mainly by CYP3A, but CYP1A2 also contributes. Pimozide metabolism is likely to be subject to interindividual variabilityin CYP3A and CYP1A2 expression and to drug interactions involving these isoforms. Pimozide itself may inhibit the metabolism of drugs that are substrates of CYP2D6.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 20/01/20 alle ore 10:20:43