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Titolo:
In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P4502C9 (CYP2C9)
Autore:
Wen, X; Wang, JS; Kivisto, KT; Neuvonen, PJ; Backman, JT;
Indirizzi:
Univ Helsinki, Dept Clin Pharmacol, FIN-00290 Helsinki, Finland Univ Helsinki Helsinki Finland FIN-00290 ol, FIN-00290 Helsinki, Finland Univ Helsinki, Cent Hosp, Helsinki, Finland Univ Helsinki Helsinki Finland v Helsinki, Cent Hosp, Helsinki, Finland
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 5, volume: 52, anno: 2001,
pagine: 547 - 553
SICI:
0306-5251(200111)52:5<547:IVEOVA>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; IN-VITRO; DRUG-INTERACTIONS; PLASMA-LEVELS; PHARMACOKINETICS; PHENYTOIN; METABOLISM; AMITRIPTYLINE; CARBAMAZEPINE; SODIUM;
Keywords:
CYP2C9; cytochrome P450; inhibition; interaction; valproic acid;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Backman, JT Univ Helsinki, Dept Clin Pharmacol, Haartmaninkatu 4, FIN-00290 Helsinki, Finland Univ Helsinki Haartmaninkatu 4 Helsinki Finland FIN-00290 and
Citazione:
X. Wen et al., "In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P4502C9 (CYP2C9)", BR J CL PH, 52(5), 2001, pp. 547-553

Abstract

Aims To evaluate the potency and specificity of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes. Methods Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform specific marker reactions were measured: phenacetin O-deethylase (CYN1A2), coumarin 7-hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), S-mephenytoin 4'-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1) and midazolam 1'-hydroxylase (CYP3A4). Results Valproic acid competitively inhibited CYP2C9 activity with a K-i value of 600 mum. In addition, valproic acid slightly inhibited CYP2C19 activity (K-i = 8553 muM, mixed inhibition) and CYP3A4 activity (K-i=7975 muM, competitive inhibition). The inhibition of CYP2A6 activity by valproic acidwas time-, concentration- and NADPH-dependent (K-t = 9150 muM, K-inact = 0.048 min(-1)), consistent with mechanism-based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed. Conclusions Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 call explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co-administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in significant drug interactions.

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Documento generato il 02/04/20 alle ore 06:41:53