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Titolo:
METABOLISM OF DEXFENFLURAMINE IN HUMAN LIVER-MICROSOMES AND BY RECOMBINANT ENZYMES - ROLE OF CYP2D6 AND 1A2
Autore:
HARITOS VS; CHING MS; GHABRIAL H; GROSS AS; TAAVITSAINEN P; PELKONEN O; BATTAGLIA SE; SMALLWOOD RA; AHOKAS JT;
Indirizzi:
RMIT UNIV,KEY CTR APPL & NUTR TOXICOL,GPO BOX 2476 V MELBOURNE VIC 3001 AUSTRALIA RMIT UNIV,KEY CTR APPL & NUTR TOXICOL MELBOURNE VIC 3001 AUSTRALIA UNIV MELBOURNE,AUSTIN & REPATRIAT MED CTR,DEPT MED PARKVILLE VIC 3052AUSTRALIA ROYAL N SHORE HOSP,DEPT CLIN PHARMACOL SYDNEY NSW AUSTRALIA UNIV OULU,DEPT PHARMACOL & TOXICOL OULU FINLAND
Titolo Testata:
Pharmacogenetics
fascicolo: 5, volume: 8, anno: 1998,
pagine: 423 - 432
SICI:
0960-314X(1998)8:5<423:MODIHL>2.0.ZU;2-O
Fonte:
ISI
Lingua:
ENG
Soggetto:
D-FENFLURAMINE; D-NORFENFLURAMINE; RAT; PHENTERMINE; DERIVATIVES; MECHANISMS; INHIBITION; OBESITY; YEAST;
Keywords:
DEXFENFLURAMINE; CYP2D6; CYP1A2; HUMAN LIVER MICROSOMES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
25
Recensione:
Indirizzi per estratti:
Citazione:
V.S. Haritos et al., "METABOLISM OF DEXFENFLURAMINE IN HUMAN LIVER-MICROSOMES AND BY RECOMBINANT ENZYMES - ROLE OF CYP2D6 AND 1A2", Pharmacogenetics, 8(5), 1998, pp. 423-432

Abstract

Dexfenfluramine has been widely used as an appetite suppressant in the treatment of obesity. It was recently shown that the apparent non-renal clearance of dexfenfluramine was significantly lower in poor metabolizers than in extensive metabolisers of debrisoquine which suggestedthe involvement of the polymorphically expressed enzyme, CYP2D6, in dexfenfluramine metabolism, In this study, human liver microsomes and yeast-expressed recombinant enzymes were used to examine dexfenfluramine metabolism in vitro, In human liver microsomes, the major product ofdexfenfluramine was nordexfenfluramine with lesser amounts of a novelmetabolite, N-hydroxynordexfenflaramine, and ketone and alcohol derivatives being formed, Eadie-Hofstee plots (v against v/[s]) of nordexfenfluramine formation between 1 and 1000 mu M substrate concentration were biphasic in three of four liver microsome samples examined, With mean K-m values of 3 and 569 mu M for the high and low affinity enzymes, respectively. At a substrate concentration (0.5 mu M) around the known therapeutic plasma concentration there was negligible inhibition ofmicrosomal dexfenfluramine N-dealkylation by sulphaphenazole and ketoconazole, but between 33 and 100% inhibition by quinidine, and 0-58% inhibition by 7,8-naphthoflavone in seven liver samples. In human livermicrosomes, there was also a significant correlation (r(s) = 0.79, n = 10, P < 0.01) between dextromethorphan O-demethylation and dexfenfluramine (at 1 mu M) N-dealkylation activities, Dexfenfluramine was a specific inhibitor (IC50 46 mu M) of CYP2D6-mediated dextromethorphan O-demethylation in human liver microsomes but did not appreciably inhibit six other cytochrome P450 isoform-selective activities for CYP1A2, 2A6, 2C9, 2C19, 2E1 and 3A activities in human liver microsomes, Yeast-expressed recombinant human CYP2D6 metabolized dexfenfluramine with high affinity (K-m 1.6 mu M, V-max 0.18 nmol min(-1) nmol P450(-1)) to nordexfenfluramine which was the sole product observed. Recombinant CYP1A2 was a lower affinity enzyme (K-m 301 mu M, V-max 1.12 nmol min(-1)nmol P450(-1)) and produced nordexfenfluramine with small amounts of N-hydroxynordexfenfluramine, This is the first detailed study to examine the in-vitro metabolism of dexfenfluramine in human liver microsomes and by recombinant human P450s, We were able to identify CYP2D6 (high affinity) and CYP1A2 (low affinity) as the major enzymes catalysing the N-dealkylation of dexfenfluramine in human liver microsomes. Pharmacogenetics 8:423-432 (C) 1998 Lippincott Williams & Wilkins.

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Documento generato il 29/03/20 alle ore 15:43:44