Characterization of the cytochrome P450 isoenzymes involved in the in vitro N-dealkylation of haloperidol

British Journal of Clinical Pharmacology
L P PanF M Belpaire

Abstract

The present study was carried out to identify the cytochrome P450 isoenzyme(s) involved in the N-dealkylation of haloperidol (HAL). In vitro studies were performed using human liver microsomes and c-DNA-expressed human P450 isoforms. N-dealkylation of HAL was assessed by measuring the formation of 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP). There was a tenfold variation in the extent of CPHP formation amongst the nine human liver microsomal preparations. The CPHP formation rates as a function of substrate concentration, measured in three livers, followed monophasic enzyme kinetics. Km and Vmax values ranged respectively from 50 to 78 microM and from 180 to 412 pmol mg-1 min-1 CPHP formation rates in the nine liver preparations were significantly correlated with dextromethorphan N-demethylase activity (a marker of CYP3A4 activity), but not with the activity of dextromethorphan O-demethylase (CYP2D6), phenacetin O-deethylase (CYP1A2) or tolbutamide hydroxylase (CYP2C9). Ketoconazole, an inhibitor of CYP3A4, inhibited competitively CPHP formation (Ki=0.1 microM), whereas sulphaphenazole (CYP2C9), furafylline (CYP1A2) and quinidine (CYP2D6) gave only little inhibition (IC50 > 100 microM). CPHP formation was, moreover, enhanced b...Continue Reading

Citations

Aug 26, 1999·Drug Metabolism Reviews·M Strolin Benedetti, M Bani
Mar 10, 2000·Clinical Pharmacokinetics·K VenkatakrishnanD J Greenblatt
Feb 13, 2001·British Journal of Clinical Pharmacology·J G ShinD A Flockhart
Nov 16, 2002·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Aleksandra GaletinJ Brian Houston
Sep 30, 2005·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Y HaraT Yokoi
Dec 20, 1999·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·M WatanabeS Kobayashi
May 9, 2002·Drug Metabolism Reviews·Slobodan Rendic
Sep 25, 2003·European Journal of Drug Metabolism and Pharmacokinetics·Jin ShimakuraHiroshi Kanamaru
Aug 18, 2010·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·David J GreenblattLisa L von Moltke
Feb 22, 2011·European Journal of Drug Metabolism and Pharmacokinetics·Siamak Cyrus KhojastehAnthony Y H Lu
Sep 23, 2014·Journal of Breath Research·Susanne von GrafensteinKlaus R Liedl
Dec 9, 1998·Drug Metabolism Reviews·E UsukiN Castagnoli
Aug 16, 2003·British Journal of Clinical Pharmacology·Tohru OhnumaHeii Arai
Mar 8, 2005·Drug Metabolism Reviews·Shufeng ZhouYu-Zong Chen
Jul 7, 1999·Fundamental & Clinical Pharmacology·M WatanabeS Kobayashi
Feb 25, 2000·Therapeutic Drug Monitoring·K Otani, T Aoshima
Jul 8, 2009·Applied Biochemistry and Biotechnology·Sepuri Asha, Maravajhala Vidyavathi
Oct 27, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yukiko KatoTsuyoshi Yokoi
Jun 12, 1999·Therapeutic Drug Monitoring·K ShimodaS Takahashi
Mar 12, 2013·ISRN Pharmacology·Guillermo GervasiniJulio Benitez

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