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Titolo:
Comparison of (S)-mephenytoin and proguanil oxidation in vitro: contribution of several CYP isoforms
Autore:
Coller, JK; Somogyi, AA; Bochner, F;
Indirizzi:
Univ Adelaide, Dept Expt & Clin Pharmacol, Adelaide, SA 5005, Australia Univ Adelaide Adelaide SA Australia 5005 ol, Adelaide, SA 5005, Australia
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 2, volume: 48, anno: 1999,
pagine: 158 - 167
SICI:
0306-5251(199908)48:2<158:CO(APO>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER-MICROSOMES; S-MEPHENYTOIN HYDROXYLATION; GENETIC-DEFECT; CYTOCHROME-P450 INHIBITORS; CAUCASIAN POPULATIONS; POOR METABOLIZERS; CYP2C19 GENOTYPE; POLYMORPHISM; IDENTIFICATION; CYCLOGUANIL;
Keywords:
(S)-mephenytoin; CYP1A2; CYP2C19; CYP3 A4; genotype; human liver microsomes; proguanil;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
30
Recensione:
Indirizzi per estratti:
Indirizzo: Coller, JK Univ Adelaide, Dept Expt & Clin Pharmacol, Adelaide, SA 5005, Australia Univ Adelaide Adelaide SA Australia 5005 e, SA 5005, Australia
Citazione:
J.K. Coller et al., "Comparison of (S)-mephenytoin and proguanil oxidation in vitro: contribution of several CYP isoforms", BR J CL PH, 48(2), 1999, pp. 158-167

Abstract

Phi Phi Aims To compare the oxidative metabolism of (S)-mephenytoin and proguanil in vitro and to determine the involvement of various cytochrome P450 isoforms. Methods The kinetics of the formation of 4'-hydroxymephenytoin and cycloguanil in human liver microsomes from 10 liver samples were determined, and inhibition of formation was studied using specific chemical inhibitors and monoclonal antibodies directed towards specific CYP450 isoforms. Expressed CYP450 enzymes were used to characterize further CYP isoform contribution invitro. Livers were genotyped for CYP2C19 using PCR amplification of genomic DNA followed by restriction endonuclease digestion. Results AU livers were wildtype with respect to CYP2C19, except HLS#5 whose genotype was CYP2C19z star 1/CYP2C19 star 2. The K-m, V-max and CLint values for the formation of 4'-hydroxymephenytoin from (S)-mephenytoin and theformation of cycloguanil fl-om proguanil ranged from 50.8 to 51.6 and 43-380 mu M 1.0-13.9 and 0.5-2.5 nmol mg(-1) h(-1), and 20.2-273.8 and 2.7-389 mu l h(-1) mg, respectively. There was a significant association between the V-max values of cycloguanil and 4'-hydroxymephenytoin formation (r(s)=0.95, P=0.0004). Cycloguanil formation was inhibited significantly by omeprazole (CYP2C19/3A), troleandomycin (CYP3A), diethyldithiocarbamate (CYP2E1/3A), furafylline (CYP1A2), and (S)-mephenytoin, 4'-Hydroxymephenytoin formation was inhibited significantly by omeprazole, diethyldithiocarbamate, proguanil, furafylline, diazepam, troleandomycin, and sulphaphenazole (CYP2C9). Human CYP2E1 and CYP3A4 monoclonal antibodies did not inhibit the formation of cycloguanil or 4'-hydroxymephenytoin, and cycloguanil was formed by expressed CYP3A4 and CYP2C19 supersomes. However, only expressed CYP2C19 and CYP2C19 supersomes formed 4'-hydroxymephenytoin. Conclusions The oxidative metabolism of (S)-mephenytoin and proguanil in vitro is catalysed by CYPs 2C19 and 1A2, with the significant association between V-max values suggesting that the predominant enzymes involved in bothreactions are similar. However the degree of selectively of both drugs forCYP isoforms needs further investigation, particularly the involvement of CYP3A4 in the metabolism of proguanil. We assert that proguanil may not be a suitable alternative to (S)-mephenytoin as a probe drug for the CYP2C19 genetic polymorphism.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 09:20:25