title: Metabolism of beta-arteether to dihydroqinghaosu by human liver microsomes and recombinant cytochrome P450.
abstract: beta-Arteether (AE) is an endoperoxide sesquiterpene lactone derivative currently being developed for the treatment of severe, complicated malaria caused by multidrug-resistant Plasmodium falciparum. Studies were undertaken to determine which form(s) of human cytochrome P-450 catalyze the conversion of beta-arteether to its deethylated metabolite, dihydroqinghaosu (DQHS), itself a potent antimalarial compound. In human liver microsomes, AE was metabolized to DQHS with a Km of 53.7 +/- 29.5 microM and a Vmax of 1.64 +/- 1. 78 nmol DQHS/min/mg protein. AE biotransformation to DQHS was inhibited by ketoconazole and troleandomycin. Ketoconazole was a competitive inhibitor, with an apparent Ki of 0.33 +/- 0.11 microM. Because AE is being developed for patients who fail primary treatment, it is possible that AE may be involved in life-threatening drug-drug interactions, such as the associated cardiotoxicity of mefloquine and quinidine. Coincubation of AE with other antimalarials showed mefloquine and quinidine to be competitive inhibitors with a mean Ki of 41 and 111 microM, respectively. Metabolism of AE using human recombinant P450s provided evidence that cytochrome P450s 2B6, 3A4, and 3A5 were the primary isozymes responsible for its deethylation. CYP3A4 metabolized AE to dihydroqinghaosu at a rate approximately 10 times that of CYP2B6 and approximately 4.5-fold greater than that of CYP3A5. These results demonstrate that CYP3A4 is the primary isozyme involved in the metabolism of AE to its active metabolite, DQHS, with secondary contributions by CYP2B6 and -3A5.
authors.affiliation: Walter Reed Army Institute of Research, Department of Pharmacology, Washington, DC 20307-5100, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Grace
authors.forename: A J
authors.initials: AJ
authors.lastname: Aguilar
authors.forename: K M
authors.initials: KM
authors.lastname: Trotman
authors.forename: J O
authors.initials: JO
authors.lastname: Peggins
authors.forename: T G
authors.initials: TG
authors.lastname: Brewer
mesh_terms: D000962:Antimalarials / Q000378:metabolism*; D037621:Artemisinins; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism*; D012717:Sesquiterpenes / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D012717:Sesquiterpenes; C039060:artenimol; D003577:Cytochrome P-450 Enzyme System; C055141:artemotil