METABOLISM OF BETA-ARTEETHER TO DIHYDROQINGHAOSU BY HUMAN LIVER-MICROSOMES AND RECOMBINANT CYTOCHROME-P450

beta-Arteether (AE) is an endoperoxide sesquiterpene lactone derivativ e currently being developed for the treatment of severe, complicated m alaria caused by multidrug-resistant Plasmodium falciparum. Studies we re undertaken to determine which form(s) of human cytochrome P-450 cat alyze the conversion of beta-arteether to its deethylated metabolite, dihydroqinghaosu (DQHS), itself a potent antimalarial compound. In hum an liver microsomes, AE was metabolized to DQHS with a K-m of 53.7 +/- 29.5 mu M and a V-max of 1.64 +/- 1.78 nmol DQHS/min/mg protein. AE b iotransformation to DQHS was inhibited by ketoconazole and troleandomy cin. Ketoconazole was a competitive inhibitor, with an apparent K-i of 0.33 +/- O.11 mu M. Because AE is being developed for patients who fa il primary treatment, it is possible that AE may be involved in life-t hreatening drug-drug interactions, such as the associated cardiotoxici ty of mefloquine and quinidine, Coincubation of AE with other antimala rials showed mefloquine and quinidine to be competitive inhibitors wit h a mean K-i of 41 and 111 mu M, respectively. Metabolism of AE using human recombinant P450s provided evidence that cytochrome P450s 2B6, 3 A4, 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 similar to 4.5-fold greater than that of CYP 3A5. These results demonstrate that CYP3A4 is the primary isozyme invo lved in the metabolism of AE to its active metabolite, DQHS, with seco ndary contributions by CYP2B6 and -3A5.