title: An investigation of the interaction between halofantrine, CYP2D6 and CYP3A4: studies with human liver microsomes and heterologous enzyme expression systems.
abstract: 1. We have assessed the interaction of the antimalarial halofantrine with cytochrome P450 (CYP) enzymes in vitro, with the use of microsomes from human liver and recombinant cell lines. 2. Rac-halofantrine was a potent inhibitor (IC50 = 1.06 microM, Ki = 4.3 microM) of the 1-hydroxylation of bufuralol, a marker for CYP2D6 activity. Of a group of structurally related antimalarials tested, only quinidine (IC50 = 0.04 microM) was more potent. 3. Microsomes prepared from recombinant CYP2D6 and CYP3A4 cell lines were shown to catalyse halofantrine N-debutylation. 4. The metabolism of halofantrine to its N-desbutyl metabolite by human liver microsomes showed no correlation with CYP2D6 genotypic or phenotypic status and there was no consistent inhibition by quinidine. 5. The rate of halofantrine metabolism showed a significant correlation with both CYP3A4 protein levels (r = 0.88, P = 0.01) and the rate of felodipine metabolism (r = 0.86, P = 0.013), a marker substrate for CYP3A4 activity. Inhibition studies showed that ketoconazole is a potent inhibitor of halofantrine metabolism (IC50 = 1.57 microM). 6. In conclusion, we have demonstrated that halofantrine is a potent inhibitor of CYP2D6 in vitro and can also be metabolised by the enzyme. However, in human liver microsomes it appears to be metabolised largely by CYP3A4.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Liverpool, UK.
authors.forename: R C
authors.initials: RC
authors.lastname: Halliday
authors.forename: B C
authors.initials: BC
authors.lastname: Jones
authors.forename: D A
authors.initials: DA
authors.lastname: Smith
authors.forename: N R
authors.initials: NR
authors.lastname: Kitteringham
authors.forename: B K
authors.initials: BK
authors.lastname: Park
mesh_terms: D000478:Alkylation; D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology; D003001:Cloning, Molecular; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004983:Ethanolamines / Q000378:metabolism; D015736:Felodipine / Q000494:pharmacology; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010616:Phenanthrenes / Q000378:metabolism* / Q000494:pharmacology; D011802:Quinidine / Q000378:metabolism; D013619:Tacrine / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000962:Antimalarials; D065607:Cytochrome P-450 Enzyme Inhibitors; D004983:Ethanolamines; D010616:Phenanthrenes; D013619:Tacrine; C010831:bufuralol; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D015736:Felodipine; C023768:halofantrine