title: Studies on the metabolism of haloperidol (HP): the role of CYP3A in the production of the neurotoxic pyridinium metabolite HPP+ found in rat brain following ip administration of HP.
abstract: The levels of haloperidol (HP) and its pyridinium metabolite HPP+ were estimated in plasma and brain tissues of rats treated i.p. with HP (10 mg/kg). HP and HPP+ levels in plasma decreased linearly during the 0-3 hour period following drug administration. On the other hand, HPP+ levels in brain tissues increased gradually during the same period. HPP+ levels in brain tissues increased further when HP (10 mg/kg) was injected for three consecutive days. The formation of HPP+ also was studied in rat brain mitochondrial and liver microsomal preparations. Enzyme activity responsible for the conversion of HP to HPP+ was not found in brain mitochondria. Liver microsomal enzymes catalyzed the oxidation of HP and its tetrahydropyridine dehydration product HPTP to HPP+ with about the same efficiency. Studies employing several cytochrome P450 inhibitors and anti-cytochrome P450 antibodies were carried out in an effort to identify the forms of cytochrome P450 that are responsible for catalyzing the oxidation of HP and HPTP to HPP+. The formation of HPP+ in liver microsomes was strongly inhibited by ketoconazole and nifedipine and by an anti-CYP3A antibody. These results suggest that formation of HPP+ from HP and HPTP in rat liver microsomes is catalyzed mainly by CYP3A although the participation of other P450 forms cannot be ruled out.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobegakuin University, Kobe, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Igarashi
authors.forename: F
authors.initials: F
authors.lastname: Kasuya
authors.forename: M
authors.initials: M
authors.lastname: Fukui
authors.forename: E
authors.initials: E
authors.lastname: Usuki
authors.forename: N
authors.initials: N
authors.lastname: Castagnoli
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001711:Biotransformation; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000906:Antibodies; D014150:Antipsychotic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011726:Pyridinium Compounds; C085216:N-(4'-fluorobutyrophenone)-4-(4-chlorophenyl)pyridinium; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019392:Cytochrome P-450 CYP2E1; D009543:Nifedipine; D006220:Haloperidol; D007654:Ketoconazole