title: Metabolism of artelinic acid to dihydroqinqhaosu by human liver cytochrome P4503A.
abstract: 1. Artelinic acid (AL), a water-soluble artemisinin analogue for treatment of multidrug resistant malaria, is metabolized to the active metabolite dihydroqinghaosu (DQHS) solely by CYP3A4/5. Although AL is not metabolized by CYP2C9, it does inhibit diclofenac 4-hydroxylase activity with an IC50 = 115 microM. Interestingly, AL activates CYP2D6-mediated bufuralol metabolism in human liver microsomes but not recombinant CYP2D6-Val by approximately 30% at AL concentrations up to 100 microM. 2. In human liver microsomes, AL is metabolized to DQHS with a Km = 157 +/- 44 microM and Vmax = 0.77 +/- 0.56 nmol DQHS/min/mg protein. Human recombinant CYP3A4 catalysed the conversion of AL to DQHS with a Km = 102 +/- 23 microM and a Vmax = 1.96 +/- 0.38 nmol DQHS/min/nmol P450. The kinetic parameters (Km and Vmax) for DQHS formation from CYP3A5 were 189 +/- 19 microM and 3.60 +/- 0.42 nmol DQHS/min/nmol P450 respectively. 3. Inhibition studies suggest that azole antifungals and calcium channel blockers may present clinically significant drug drug interactions. In human liver microsomes, ketoconazole and miconazole were potent competitive inhibitors of DQHS formation with a Ki = 0.028 and 0.124 microM respectively. Verapamil is a non-competitive inhibitor of DQHS formation in human liver microsomes with a Ki = 15 microM.
authors.affiliation: Department of Pharmacology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Grace
authors.forename: D J
authors.initials: DJ
authors.lastname: Skanchy
authors.forename: A J
authors.initials: AJ
authors.lastname: Aguilar
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000494:pharmacology; D000962:Antimalarials / Q000378:metabolism*; D037621:Artemisinins; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism*; D004338:Drug Combinations; D004347:Drug Interactions; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006035:Glycyrrhiza; D006801:Humans; D008658:Inactivation, Metabolic; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008825:Miconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000187:drug effects / Q000378:metabolism*; D029596:Paeonia; D011802:Quinidine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012717:Sesquiterpenes / Q000378:metabolism*; D013426:Sulfaphenazole / Q000494:pharmacology; D014217:Troleandomycin / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D012717:Sesquiterpenes; D014665:Vasodilator Agents; C038462:shakuyaku-kanzoh-toh; C062768:artelinic acid; D013426:Sulfaphenazole; C039060:artenimol; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D014700:Verapamil; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D011802:Quinidine; D007654:Ketoconazole