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Titolo:
Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol
Autore:
Shin, JG; Kane, K; Flockhart, DA;
Indirizzi:
Georgetown Univ, Med Ctr, Dept Med, Div Clin Pharmacol, Washington, DC 20007 USA Georgetown Univ Washington DC USA 20007 armacol, Washington, DC 20007 USA Georgetown Univ, Med Ctr, Dept Pharmacol, Div Clin Pharmacol, Washington, DC 20007 USA Georgetown Univ Washington DC USA 20007 armacol, Washington, DC 20007 USA
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 1, volume: 51, anno: 2001,
pagine: 45 - 52
SICI:
0306-5251(200101)51:1<45:PIOCBH>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
NEUROTOXIC PYRIDINIUM METABOLITE; HUMAN-LIVER-MICROSOMES; PSYCHIATRIC-PATIENTS; SCHIZOPHRENIC-PATIENTS; CYTOCHROME-P450 3A4; DRUG-INTERACTIONS; N-DEALKYLATION; PLASMA; INVOLVEMENT; OXIDATION;
Keywords:
CYP2D6; enantiomer; haloperidol; inhibition; interaction; metabolites; reduced haloperidol;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Flockhart, DA Georgetown Univ, Med Ctr, Dept Med, Div Clin Pharmacol, 3900Reservoir Rd NW, Washington, DC 20007 USA Georgetown Univ 3900 Reservoir Rd NW Washington DC USA 20007
Citazione:
J.G. Shin et al., "Potent inhibition of CYP2D6 by haloperidol metabolites: stereoselective inhibition by reduced haloperidol", BR J CL PH, 51(1), 2001, pp. 45-52

Abstract

Aims We evaluated the inhibitory effect of haloperidol and its metaboliteson CYP2D6 activity in order to better understand the potential role of these metabolites in drug interactions involving haloperidol. Methods The inhibitory effects of haloperidol and five of its metabolites on dextrorphan formation from dextromethorphan, a marker probe of CYP2D6 activity, were measured in human liver microsomal preparations. Apparent kinetic parameters for enzyme inhibition were determined by nonlinear regression analysis of the data. Results Racemic reduced haloperidol and its metabolite, RHPTP competitively inhibited dextromethorphan O-demethylation with estimated K-i values (0.24 muM and 0.09 muM, respectively) that were substantially lower than that of haloperidol (0.89 muM) The inhibitory effect of S(-)-reduced haloperidol was more potent than the R(S)enantiomer, with estimated K-i values of 0.11 muM and 1.1 muM, respectively. The pyridinium metabolite of haloperidol, HPP+ inhibited the enzyme activity noncompetitively with a K-i value of 0.79 muM. The N-dealkylated metabolites of haloperidol (FBPA and CPHP) had a diminished inhibitory potency. While FBPA showed no notable inhibitory effect on dextrorphan formation, CPHP showed moderate competitive inhibition with a K-i value of 20.9 muM. Conclusions The principal metabolites of haloperidol inhibit CYP2D6, suggesting that they might contribute to the inhibitory effects of the drug. Reduced haloperidol seems to inhibit CYP2D6 activity in an enantioselective manner with the physiologically occurring S(-) enantiomer being more potent.

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Documento generato il 20/11/19 alle ore 03:46:05