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Titolo:
The xenobiotic inhibitor profile of cytochrome P4502C8
Autore:
Ong, CE; Coulter, S; Birkett, DJ; Bhasker, CR; Miners, JO;
Indirizzi:
Flinders Med Ctr, Dept Clin Pharmacol, Adelaide, SA, Australia Flinders Med Ctr Adelaide SA Australia harmacol, Adelaide, SA, Australia Flinders Univ S Australia, Adelaide, SA 5001, Australia Flinders Univ S Australia Adelaide SA Australia 5001 , SA 5001, Australia
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 6, volume: 50, anno: 2000,
pagine: 573 - 580
SICI:
0306-5251(200012)50:6<573:TXIPOC>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER-MICROSOMES; IN-VITRO METABOLISM; HUMAN HEPATIC MICROSOMES; HUMAN DRUG-METABOLISM; N-DEMETHYLATION; OXIDATION; ENZYMES; 3A4; BIOTRANSFORMATION; PARTICIPATION;
Keywords:
cytochrome P450; CYP2C8; cytochrome P450 inhibitors; drug interactions;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Miners, JO Flinders Univ S Australia, Med Ctr, Dept Clin Pharmacol, Bedford Pk, SA 5042, Australia Flinders Univ S Australia Bedford Pk SA Australia5042 stralia
Citazione:
C.E. Ong et al., "The xenobiotic inhibitor profile of cytochrome P4502C8", BR J CL PH, 50(6), 2000, pp. 573-580

Abstract

Aims To investigate inhibition of recombinant CYP2C8 by: (i) prototypic CYP isoform selective inhibitors (ii) imidazole/triazole antifungal agents (known inhibitors of CYP), and (iii) certain CYP3A substrates (given the apparent overlapping substrate specificity of CYP2C8 and CYP3A). Methods CYP2C8 and NADPH-cytochrome P450 oxidoreductase were coexpressed in Spodoptera frugiperda (Sf21) cells using the baculovirus expression system. CYP isoform selective inhibitors, imidazole/triazole antifungal agents and CYP3A substrates were screened for their inhibitory effects on CYP2C8-catalysed torsemide tolymethylhydroxylation and, where appropriate, the kinetics of inhibition were characterized. The conversion of torsemide to its tolylmethylhydroxy metabolite was measured using an h.p.l.c. procedure. Results At concentrations of the CYP inhibitor 'probes' employed for isoform selectivity, only diethyldithiocarbamate and ketoconazole inhibited CYP2C8 by > 10%. Ketoconazole, at an added concentration of 10 muM, inhibited CYP2C8 by 89%. Another imidazole, clotrimazole, also potently inhibited CYP2C8. Ketoconazole and clotrimazole were both noncompetitive inhibitors of CYP2C8 with apparent K-i values of 2.5 muM. The CYP3A substrates amitriptyline, quinine, terfenadine and triazolam caused near complete inhibition (82-91% of control activity) of CYP2C8 at concentrations five-fold higher than the known CYP3A K-m. Kinetic studies with selected CYP3A substrates demonstrated that most inhibited CYP2C8 noncompetitively. Apparent K-i values for midazolam, quinine, terfenadine and triazolam ranged from 5 to 25 muM. Conclusions Inhibition of CYP2C8 occurred at concentrations of ketoconazole and diethyldithiocarbamate normally employed for selective inhibition of CYP3A and CYP2E1, respectively. Some CYP3A substrates have the capacity to inhibit CYP2C8 activity and this may have implications for inhibitory drug interactions in vivo.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 31/03/20 alle ore 22:35:39